Criteria Specification Registry

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Criteria Specification

ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0

Description : RPGR specifications

Version : 1.0.0 Release Notes :

Pilot Rules Submitted as of 01/22/2024.

X-linked Inherited Retinal Disease VCEP

Released

5/16/2025

14:03:00

Rules for RPGR

In addition to the specific criteria for codes listed below, the VCEP has adopted the point-based combining scoring in Table 2 and Table 3 of PMID: 32720330. Table 2 assigns points for pathogenic (0 for indeterminate, 1 for supporting, 2 for moderate, 4 for strong, and 8 for very strong), and benign (0 for indeterminate, -1 for supporting, -2 for moderate, -4 for strong, and -8 for very strong) codes. Table 3 provides final categories of Pathogenic (>= 10), Likely Pathogenic (6-9), Uncertain (0-5), Likely Benign (-1 to -6), Benign (<=7). There are two transcripts for RPGR: NM_001034853.2 is the retinal specific transcript for which the gene-disease association has been defined and NM_000328.3 which is more broadly expressed in other tissues. The two transcripts overlap for exons 1 to 15. NM_001034853.2 reads through the exon 15 terminal splice site and continues into ORF15. NM_000328.3 splices from exon 15 to exon 16 and includes exons 16 to 19. These rules have been specified for the ORF15 transcript with ACMG/AMP default specifications for NM_000328.3 exons 16 to 19.

Gene: RPGR (HGNC:10295) HGNC Name: retinitis pigmentosa GTPase regulator Transcripts: NM_001034853.2 Disease: RPGR-related retinopathy (MONDO:0100437) Mode of Inheritance: X-linked inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. VCEP Specifications: Use SVI recommendations (PMID 30192042) with modifications as shown in the RPGR PVS1 Decision Tree figure attached. Stand Alone Very Strong Use SVI recommendations (PMID 30192042, and PMID 37352859) with modifications as shown in the RPGR PVS1 Decision Tree with splice guidance figures attached. NM_001034853.2 - Transcript isoform C reads through the splice site at the end of exon 15 (ORF15) creating a longer protein sequence with a repetitive region in the 3’ end. This is the transcript expressed in retina. NM_000328.3 - Transcript isoform A includes 19 exons and produces a shorter mRNA and protein sequence than isoform C. Variants in exons 16 to 19 are not associated with RPGR-related retinopathy. PVS1_Met designation for variants predicted to undergo NMD, nonsense or frameshift variants that disrupt the critical function of glutamylation in ORF15, or variants causing skipped or deleted exons that affect regions critical to protein function. Modification Type: Gene-specific,Strength Strong PVS1_Strong designation for variants that remove more than 10% of the protein and are not expected to lead to NMD. Modification Type: Gene-specific,Strength Moderate PVS1_Moderate designation for initiation codon variants with upstream pathogenic variants of closest potential in-frame start codon or for variants in NM_00328.3 which remove less than 10% of the protein and are not expected to lead to NMD. Modification Type: Gene-specific,Strength Supporting PVS1_Supporting designation for initiation codon variants without upstream pathogenic variants of closest potential in-frame start codon. Modification Type: Gene-specific,Strength Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. VCEP Specifications: See RPGR specific PVS1 Decision Tree. Stand Alone Very Strong Strong Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change. Comparison variant must have been evaluated by the X-linked IRD VCEP using these rules and established as a pathogenic variant and classified as such. For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other. Same predicted splicing impact as a previously classified Pathogenic variant. Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the same position that has been designated Pathogenic. Used in conjunction with PVS1 for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and that have a comparable variant within the same splice donor/acceptor +/-1,2 dinucleotide that has been designated Pathogenic. Specific combinations are found in _RPGR_-specific PVS1 Decision Tree part (b) (Table 2 from Walker 2023). Modification Type: Clarification,General recommendation Moderate Same amino acid change as a previously established Likely Pathogenic variant regardless of nucleotide change. Comparison variant must have been evaluated by the X-linked IRD VCEP using these rules and established as likely pathogenic variant and classified as such. For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other. Same predicted splicing impact as a previously classified Pathogenic variant. Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the same position that has been designated Likely Pathogenic. Used in conjunction with PVS1_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and that have a comparable variant within the same splice donor/acceptor motif (but outside of the +/-1,2 dinucleotide) that has been designated Pathogenic. Specific combinations are found in _RPGR_-specific PVS1 Decision Tree part (b) (Table 2 from Walker 2023). Modification Type: Clarification,General recommendation Supporting Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant within the same motif that has been designated Likely Pathogenic. Used in conjunction with PVS1 or PVS1_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable Likely Pathogenic or Pathogenic variant either within the same splice site donor/acceptor motif, outside the +/-1,2 dinucleotide, or at the +/-1,2 dinucleotide. Specific combinations are found in _RPGR_-specific PVS1 Decision Tree part (b) (Table 2 from Walker 2023). Modification Type: Clarification,General recommendation Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. VCEP Specifications: Note that all probands being considered for any pathogenic phenotype codes (e.g. PP1, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 30, and/or decreased or absent cone and/or rod ERG / FAF responses. Affected females can be considered if they have an affected male relative described, and their relationship is consistent with an X-linked inheritance. Stand Alone Very Strong Use SVI point scale for counting cases (see Table 1 on PS2_PM6 table), use option 3 “Phenotype consistent with gene but not hightly specific and high genetic heterogeneity.” Confirmed de novo with confirmed maternity worth 0.5 points per proband. Total 4.0 points to use at the very strong strength. Modification Type: Gene-specific Strong Use SVI point scale for counting cases (see Table 1 on PS2_PM6 table), use option 3 “Phenotype consistent with gene but not hightly specific and high genetic heterogeneity.” Confirmed de novo with confirmed maternity worth 0.5 points per proband. Assumed de novo with assumed maternity worth 0.25 points per proband. Total 2.0 points to use at the strong strength. Modification Type: Gene-specific Moderate Use SVI point scale for counting cases (see Table 1 on PS2_PM6 table), use option 3 “Phenotype consistent with gene but not hightly specific and high genetic heterogeneity.” Confirmed de novo with confirmed maternity worth 0.5 points per proband. Assumed de novo with assumed maternity worth 0.25 points per proband. Total 1.0 points to use at the moderate strength. Modification Type: Gene-specific Supporting Use SVI point scale for counting cases (see Table 1 on PS2_PM6 table), use option 3 “Phenotype consistent with gene but not hightly specific and high genetic heterogeneity.” Confirmed de novo with confirmed maternity worth 0.5 points per proband. Assumed de novo with assumed maternity worth 0.25 points per proband. Total 0.5 points to use at the supporting strength. Modification Type: Gene-specific Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. VCEP Specifications: See excel file for details. Stand Alone Very Strong Strong Moderate Supporting Assays with OddsPath >2.1 as per the SVI recommendations¹ Applies to the following functional studies: Protein-protein interaction (PMIDs: 30622176, 20631154, 10958648, 23213406, 9990021, 36445968) Protein localization to connecting cilia (PMIDs: 30622176, 25630948). Glutamylation assays (only applicable to truncating variants in exon 15, PMIDs: 27162334, 36445968) -OR- Animal models that replicate the phenotype. Modification Type: Gene-specific Not Applicable Comments: This code is not currently applicable.
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. VCEP Specifications: Note that all probands being considered for any pathogenic phenotype codes (e.g. PP1, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 30, and/or decreased or absent cone and/or rod ERG / FAF responses. Affected females can be considered if they have an affected male relative described, and their relationship is consistent with an X-linked inheritance. Probands counted for PS4 must be unrelated to each other. Probands may overlap with PP4 probands at the supporting level. Stand Alone Very Strong Use of this code requires ≥ 8 probands and PM2_Supporting must be met. Modification Type: Gene-specific,Strength Strong Use of this code requires ≥ 6 probands and PM2_Supporting must be met. Modification Type: Gene-specific,Strength Moderate Use of this code at the moderate strength requires 3-5 probands and PM2_Supporting must be met. Modification Type: Gene-specific,Strength Supporting Use of this code at the supporting strength requires ≥ 2 probands and PM2_Supporting must be met. OR If PS4 Met at the PS4_Supporting level by 1 proband (when a separate unrelated proband has been used for PP4): This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, as well as a second apparently unrelated proband previously used for the PP4 code. Modification Type: Gene-specific,Strength Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: See PM2_Supporting.
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting Allele frequency in males ≤ 0.00005 (≤5x10^-5) in population databases. Highest allele frequency in a subpopulation should be used to assess this. Modification Type: Clarification,Gene-specific Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. VCEP Specifications: ORF15 repetitive region (amino acids 585 to 1078) should not be evaluated here. Stand Alone Very Strong Strong Use for stop loss variants in aa 1153. These variants will produce a 38 amino acid extension which was shown to have a deleterious effect (PMID:33805381, variant in c.3457). Modification Type: Gene-specific Moderate Protein length changes in exons 1-14, due to in-frame deletions/insertions in a non-repeat region. Or, in ORF15 outside of the repetitive region in amino acids 585 to 1078, due to in-frame deletions/insertions in a non-repeat region. Modification Type: Clarification,Gene-specific Supporting Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Moderate Must have 2 comparison variants reaching pathogenic classification using these specifications. - The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3, and have a Grantham score equal to or greater than the previously published variants. Modification Type: Clarification,Gene-specific Supporting Same residue as a previously established likely pathogenic variant (assessed independently of PM5). - The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3, and have a Grantham score equal to or greater than the previously published variants. Modification Type: Clarification,Gene-specific Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. VCEP Specifications: Note that all probands being considered for any pathogenic phenotype codes (e.g. PP1, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 30, and/or decreased or absent cone and/or rod ERG / FAF responses. Affected females can be considered if they have an affected male relative described, and their relationship is consistent with an X-linked inheritance. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: See PS2 for de novo data.
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. VCEP Specifications: Note that all probands being considered for any pathogenic phenotype codes (e.g. PP1, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 30, and/or decreased or absent cone and/or rod ERG / FAF responses. Affected females can be considered if they have an affected male relative described, and their relationship is consistent with an X-linked inheritance. Stand Alone Very Strong Strong Use of this code requires ≥4 meioses in >1 family Only phenotype positive relatives with the same variant identified in the proband should be counted as segregations. Modification Type: Gene-specific,Strength Moderate ≥ 3 meioses In ≥ 1 families Only phenotype positive relatives with the same variant identified in the proband should be counted as segregations. Modification Type: Gene-specific,Strength Supporting ≥ 2 meioses in the same family OR proband with affected mother Only phenotype positive relatives with the same variant identified in the proband should be countedas segregations. Modification Type: Gene-specific,Strength Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Applies to missense variants with a REVEL score above 0.932, that are not predicted to disrupt splicing (with a SpliceAI score less than 0.2). This criteria is met at the strong level. Modification Type: General recommendation Moderate Applies to missense variants with a REVEL score between 0.773 and 0.931, that are not predicted to disrupt splicing (with a SpliceAI score less than 0.2). This criteria is met at the moderate level. Modification Type: General recommendation Supporting Applies to missense variants with a REVEL score between 0.644 and 0.772 that are not predicted to disrupt splicing (with a SpliceAI score less than 0.2). For variants with SpliceAI scores greater than or equal to 0.2, in the two first or last two bases in an exon or the 6 intronic bases flanking an exon, this code is met at the supporting level. Modification Type: Clarification,General recommendation,Gene-specific Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. VCEP Specifications: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. A point system was developed to determine when there is enough information about a proband’s phenotype to qualify for use of this code (see below). Review eligible phenotype characteristics and add up points for each finding. This code can be used for a single proband. 4 or more phenotype points are required to use this code. Do not include a proband with a suspected diagnosis of more than one retinal disease. Required for use of PP4 (0 points each) Males have functional vision impairment by age 30 Decreased or absent cone and/or rod ERG or FAF responses Specific RPGR Phenotype Findings List (2 points each) Family history consistent with X-linked inheritance, no male-to male transmission Previous exome, genome or 100+ retinal dystrophy panel (that includes X-linked genes) testing that did not provide an alternative explanation for visual impairment Consistent with RPGR Findings (0.5 or 1 point each) Rod involvement relatively greater than cone involvement (1) Onset in the 1st or 2nd decade of life (ages 2-19) (1) Delayed or milder phenotype in females (1) Unlike carriers of other X-linked RP, female carriers show some retinal pathology by age 50 (usually by age 30), by abnormal fundus pigmentation, and more certainly by ERG response amplitude reduction Patient report of Night blindness/nyctalopia (0.5) Optic nerve pallor (0.5) Pigmentary retinopathy (0.5) Poor pupillary light response (0.5) Abnormal color vision (0.5) Decreased central vision acuity (0.5) Myopia (0.5) or high myopia (e.g. -6 Diopter and higher) (1.0) Photodysphoria / photophobia (0.5) Visual field constriction (0.5) Stand Alone Very Strong Strong Moderate > 8 phenotype points required; two specific criteria must be met Modification Type: Clarification,Gene-specific,Strength Supporting 4-7 phenotype points required; one specific criterion must be met. Modification Type: Clarification,Gene-specific,Strength Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone Allele frequency in males is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium in the subpopulation with the highest frequency. Modification Type: Clarification Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong Allele frequency in males is greater than expected for the disorder. Use for alleles with frequency ≥8.3x10^-5 (based on the most frequent pathogenic allele). Modification Type: Gene-specific Moderate Supporting Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong Only count males over age 30 with a documented eye examination with functional studies (normal ERG or FAF). Modification Type: Disease-specific,Gene-specific Moderate Supporting Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong For maternally inherited variants in RPGR, a variant present in a clinically verified (documented with a normal eye examination with functional studies including a normal ERG) unaffected male over age 30 could be used to establish this code. Inheritance is complicated in consanguineous families and in dual diagnoses situations so panel testing of unaffected members required to confirm presence of the variant. Modification Type: Clarification,Disease-specific,Gene-specific Moderate Supporting Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: X-linked gene.
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Use for ORF15 repetitive regions only (amino acids 585-1078). These events can be multiple and large (e.g. 9 plus 15 total 20-30 bp is known, a single 21bp event is common). Please note that ORF15 encompasses residues 585 through 1152, with UniProt identifying particularly disordered regions between 609-776, 790-906, and 989-1020. Modification Type: Clarification,Gene-specific Not Applicable
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Stand Alone criteria applies to: Missense variants: REVEL ≤ 0.003 Synonymous variants or noncoding variants: SpliceAI ≤ 0.1 Strong criteria applies to: Missense variants: REVEL between 0.004 and 0.016 Synonymous variants or noncoding variants: SpliceAI ≤ 0.1 Modification Type: General recommendation Moderate Applies to: Missense variants: REVEL between 0.017 and 0.183 Synonymous variants or noncoding variants: SpliceAI ≤ 0.1 Modification Type: General recommendation Supporting Applies to: Missense variants: REVEL between 0.184 and 0.290 Synonymous variants or noncoding variants: SpliceAI ≤ 0.1 Modification Type: General recommendation Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting Applies to: Synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.2) AND PhyloP < 0 for conservation Modification Type: Clarification,Gene-specific Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS4, PM4_Strong, PP1_Strong, PP3_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND 1 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS4, PM4_Strong, PP1_Strong, PP3_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM4_Strong, PP1_Strong, PP3_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM4_Strong, PP1_Strong, PP3_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM4_Strong, PP1_Strong, PP3_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM4_Strong, PP1_Strong, PP3_Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 1 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Benign

≥ 2 Strong (BS1, BS2, BS4, BP4_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4, BP4_Strong) AND 1 Supporting (BP3, BP4, BP7)

≥ 2 Supporting (BP3, BP4, BP7)

Files & Images

PVS1 Decision Tree for RPGR: Powerpoint file includes splice assessment and updated coordinates for SVI review.

Standard Operating Procedure - RPGR- V.7: Standard operating procedures for RPGR variant curation.

Phenotype Features - RPGR Specifications: Introduction to the phenotype features of RPGR in both affected males and carrier females (who may or may not be affected).

c.730A-T Variant Report: Pilot Variant c.730A>T curation for SVI review.

PS3 Functional Evidence - RPGR Specifications: Excel file describing functional assays as of November 2022.

RPGR PVS1 and PVS1 (RNA) Decision Tree: RPGR specific PVS1 and PVS1 (RNA) Decision Tree.

References

1. Abou Tayoun AN Pesaran T et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat (2018) 39 (11) p. 1517-1524. 10.1002/humu.23626 30192042

2. Meindl A Dry K et al. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet (1996) 13 (1) p. 35-42. 10.1038/ng0596-35 8673101

3. De Silva SR Arno G et al. The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies. Prog Retin Eye Res (2021) 82 p. 100898. 10.1016/j.preteyeres.2020.100898 32860923

4. Vervoort R Lennon A et al. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet (2000) 25 (4) p. 462-6. 10.1038/78182 10932196

5. Zhang Q Giacalone JC et al. Disruption of RPGR protein interaction network is the common feature of RPGR missense variations that cause XLRP. Proc Natl Acad Sci U S A (2019) 116 (4) p. 1353-1360. 10.1073/pnas.1817639116 30622176

6. Murga-Zamalloa CA Atkins SJ et al. Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration. Hum Mol Genet (2010) 19 (18) p. 3591-8. 10.1093/hmg/ddq275 20631154

7. Hong DH Pawlyk BS et al. Dominant, gain-of-function mutant produced by truncation of RPGR. Invest Ophthalmol Vis Sci (2004) 45 (1) p. 36-41. 10.1167/iovs.03-0787 14691151

8. Nanda A Salvetti AP et al. Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing their Potential for Retinal Gene Therapy. Genes (Basel) (2018) 9 (12) 10.3390/genes9120643 30567410

9. Rozet JM Perrault I et al. Dominant X linked retinitis pigmentosa is frequently accounted for by truncating mutations in exon ORF15 of the RPGR gene. J Med Genet (2002) 39 (4) p. 284-5. 10.1136/jmg.39.4.284 11950860

10. Pejaver V Byrne AB et al. Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria. Am J Hum Genet (2022) 109 (12) p. 2163-2177. 10.1016/j.ajhg.2022.10.013 36413997

11. Walker LC Hoya M et al. Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup. Am J Hum Genet (2023) 110 (7) p. 1046-1067. 10.1016/j.ajhg.2023.06.002 37352859

12. Tavtigian SV Harrison SM et al. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat (2020) 41 (10) p. 1734-1737. 10.1002/humu.24088 32720330

Criteria Specification

Rules for RPGR

Required for use of PP4 (0 points each)

Specific RPGR Phenotype Findings List (2 points each)

Consistent with RPGR Findings (0.5 or 1 point each)

Rules for Combining Criteria

Files & Images

References