Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0

Description : X-linked IRD Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1.

Version : 1.0.0

X-linked Inherited Retinal Disease VCEP

Released

5/16/2025

14:04:43

Rules for RS1

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). This replaces the combining rules listed below.

Gene: RS1 (HGNC:10457) HGNC Name: retinoschisin 1 Transcripts: NM_000330.4 Disease: X-linked retinoschisis (MONDO:0010725) 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. Stand Alone Very Strong Use attached RS1-specific PVS1 Decision Tree file, which has been modified from Abou Tayoun, et al., 2018 (PMID 30192042) and incorporates splice site guidance from Walker et al, 2023 (PMID 37352859). This strength applies to nonsense, frameshift, splice site, and deletion variants in NM_000330.4 c.1A to c.671C (p.Met1 to p.Cys223) and to duplications in NM_000330.4 c.1 to c. 472 (p.Met1 to p.Asp158). The structure of RS1 is important for function. The RS1 monomers have cystine disulfide bonds within a RS1 monomer and bonds with the two neighboring monomers to form an octomer substructure and bonds to the second RS1 octomer that completes the paired octomer structure. Within this structure there are a number of sites that have been shown to function in other types of protein structure stabilization. Modification Type: Gene-specific Strong Use attached RS1-specific PVS1 Decision Tree file, which has been modified from Abou Tayoun, et al., 2018 (PMID 30192042) and incorporates splice site guidance from Walker et al, 2023 (PMID 37352859). This strength applies to frameshift variants, GT--AG splice variants, deletions, duplications or nonsense variants in NM_000330.4 c.672 to c.677 (p.Asp224 to p.*225). Modification Type: Gene-specific Moderate Use attached RS1-specific PVS1 Decision Tree file, which has been modified from Abou Tayoun, et al., 2018 (PMID 30192042) and incorporates splice site guidance from Walker et al, 2023 (PMID 37352859). Modification Type: Gene-specific Supporting 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: Refer to the RS1_-specific PVS1 Decision Tree document for more complete information. Stand Alone Very Strong Strong Same amino acid change as a previously established Pathogenic variant. 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. When evaluating splicing impact, as a previously classified Pathogenic variant, Use in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI 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 RS1-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. Comparison variant must have been evaluated by the X-linked IRD VCEP using these rules and established as a 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. When evaluating splicing impact, with a previously classified Likely Pathogenic or Pathogenic variant, Use in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI score ≥0.2 and have a comparable nucleotide variant at the same position that has been designated Likely Pathogenic. Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI score ≥0.2 and have a comparable nucleotide variant within the same splice region with the same predicted impact that has been designated Pathogenic. Use in conjunction with PVS1 at any strength for variants located within splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI score ≥0.2 and a comparable nucleotide variant within the same splice motif region but outside the donor/acceptor +/-1,2 dinucleotide positions with the same predicted impact that has been designated Pathogenic. Specific combinations are found in RS1-specific PVS1 Decision Tree part (b) (Table 2 from Walker 2023). Modification Type: Clarification,General recommendation Supporting Same amino acid change as a previously established (Likely) Pathogenic variant. Comparison variant must have been evaluated by the X-linked IRD VCEP using these rules and established as a 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. When evaluating splicing impact, with a previously classified Likely Pathogenic variant, Use in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI score ≥0.2 and have a comparable nucleotide variant variant within the same splice motif region but outside the donor/acceptor +/-1,2 dinucleotide positions with the same predicted impact that has been designated Likely Pathogenic. Used in conjunction with PVS1 for variants located within the splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI score ≥0.2 and have a comparable nucleotide variant at the same splice donor/acceptor +/-1,2 dinucleotide position with the same predicted impact that has been designated Pathogenic. Use in conjunction with PVS1 for variants located within splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI score ≥0.2 and a comparable nucleotide variant within the same splice motif region but outside the donor/acceptor +/-1,2 dinucleotide positions with the same predicted impact that has been designated either Likely Pathogenic or Pathogenic. Use in conjunction with PVS1 at any strength for variants located within splice donor/acceptor +/-1,2 dinucleotide positions that have a SpliceAI score ≥0.2 and a comparable nucleotide variant within the same splice motif region but outside the donor/acceptor +/-1,2 dinucleotide positions with the same predicted impact that has been designated Likely Pathogenic. Specific combinations are found in RS1-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 probands being considered for any pathogenic phenotype codes (e.g. PP1, PP4, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 13, with either observed foveo-macular changes or ERG measurement of a subnormal B wave. Stand Alone Very Strong Use SVI point scale for counting cases (see Table 1 on PS2_PM6 table), use option 1 “Phenotype highly specific for gene.” Confirmed de novo with confirmed maternity worth 2.0 points per proband. Assumed de novo with assumed maternity worth 1.0 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 1 “Phenotype highly specific for gene.” Confirmed de novo with confirmed maternity worth 2.0 points per proband. Assumed de novo with assumed maternity worth 1.0 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 1 “Phenotype highly specific for gene.” Confirmed de novo with confirmed maternity worth 2.0 points per proband. Assumed de novo with assumed maternity worth 1.0 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 1 “Phenotype highly specific for gene.” Confirmed de novo with confirmed maternity worth 2.0 points per proband. Assumed de novo with assumed maternity worth 1.0 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 RS1 Functional Assay sheet. Stand Alone Very Strong Strong Variants tested in high quality knock-out/knock-in variant mouse lines can meet PS3 at the strong level. Modification Type: Gene-specific,Strength Moderate Supporting Use at the supporting strength for most assays (see Functional Assays Table). Modification Type: Gene-specific,Strength 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 probands being considered for any pathogenic phenotype codes (e.g. PP1, PP4, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 13, with either observed foveo-macular changes or ERG measurement of a subnormal B wave. Stand Alone Very Strong Use of this code requires 9 or more probands, each with retinoschisis. PM2_Supporting must be met. Modification Type: Gene-specific,Strength Strong Use of this code requires 5-8 probands, each with retinoschisis. PM2_Supporting must be met. Modification Type: Gene-specific,Strength Moderate Use of this code at the moderate strength requires 3-4 probands diagnosed with retinoschisis. PM2_Supporting must be met. Modification Type: Gene-specific,Strength Supporting Use of this code at the supporting strength requires 1 proband diagnosed with retinoschisis, and a second proband answering the PP4 requirements. PM2_Supporting must be met. Or 2 probands, each with retinoschisis. PM2_Supporting must be met. 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 Applies to variants in amino acids p.Cys40, p.Cys59, p.Cys63, p.Cys110, p.Cys142, p.Cys219, and p.Cys223 which form disulfide bridges required for structure of the retinoschisin monomer, dimers, or octamers. Modification Type: Gene-specific Moderate Applies to amino acids p.Glu72, p.Trp122, p.Trp163, p.Arg200, p.Glu215 which form salt bridges that are required for higher order structure of octamers and paired octamers. Modification Type: Gene-specific 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 At low frequency in males in population databases. Use <2.0x10^-6 for cut off. This is defined relative to the BA1 cutoff. 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: Use SVI specification. Stand Alone Very Strong Strong Moderate In-frame deletion/insertions smaller than one whole exon, in a non-repetitive region, or stop-loss variants. Variant must not be considered in any PVS1 criteria. Variant must also meet PM2. Modification Type: General recommendation,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 Same residue as a previously established pathogenic variant classified using these specifications (assessed independently of PM5) . The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3, and have a Grantham score equal or greater than the previously published variants. Modification Type: Clarification,Gene-specific Supporting Same residue as a previously established likely pathogenic variant classified using these specifications (assessed independently of PM5) . The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3, and have a Grantham score equal or greater than the previously published variants. Modification Type: 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, PP4, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 30, with decreased or absent cone and/or rod ERG responses. 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 probands being considered for any pathogenic phenotype codes (e.g. PP1, PP4, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 13, with either observed foveo-macular changes or ERG measurement of a subnormal B wave. Stand Alone Very Strong Strong Use of this code requires ≥3 meioses in 1 or 2 families. Only phenotype positive male relatives with the same variant identified in the proband should be counted as segregations. Modification Type: Gene-specific,Strength Moderate 2 meioses in a family (e.g. 2 brothers and mother genotyped; 3 brothers without mother's genotype; or uncle and nephew) Only phenotype positive male relatives with the same variant identified in the proband should be counted as segregations. Modification Type: Gene-specific,Strength Supporting 1 meiosis in a family Only phenotype positive male relatives with the same variant identified in the proband should be counted as 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. VCEP Specifications: Loss of function variants are underrepresented. The Z score in GnomAD is 1.66. The eligible score for this code is 0/303. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Loss of function variants are underrepresented. The Z score in GnomAD is 0.97. The pLoF eligible alleles for this code is 0/303.
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. VCEP Specifications: Use the SpliceAI flowchart included in the RS1-specific PVS1 Decision Tree file. Stand Alone Very Strong Strong Applies to missense variants with a REVEL score above 0.931, 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). Modification Type: General recommendation 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: Note that probands being considered for any pathogenic phenotype codes (e.g. PP1, PP4, PM6, PS2, PS4) at any strength must have the following phenotype characteristics: affected males should have some functional vision impairment by age 13, with a diagnosis of Retinoschisis and an image of schisis. Stand Alone Very Strong Strong Moderate A male proband diagnosed with retinoschisis by the age of 13 with visual acuity impairment, showing schisis, and having retinal detachment. Modification Type: Clarification,Gene-specific,Strength Supporting A male proband diagnosed with retinoschisis by the age of 13 with visual acuity impairment and showing schisis. 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. VCEP Specifications: Any variant meeting both BA1 and PP3 must be reviewed by the VCEP. Stand Alone Allele frequency ≥ 2x10^-4 in males in population databases (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. VCEP Specifications: Variants meeting both BS1 and PP3 must be reviewed by the VCEP. Stand Alone Very Strong Strong Allele frequency ≥ 2x10^-5 in males in population databases. - The highest allele frequency in population databases should be used 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 exam without retinoschisis. BS2_strong for variants observed in at least 3 unaffected males. 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 Comments: The many secretion assays have not tested enough benign variants to meet the threshold in PMID 31892348 Supplemental Table 1 or Supplemental Table 2.
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 Moderate Supporting Paternal inheritance is inconsistent with this gene. For RS1, unaffected males over age 10 who have been examined could be used to establish this code if they have no schisis and good acuity. Modification Type: Gene-specific 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: For this X-linked gene, only variants in cis with a pathogenic variant in RS1 in an affected male could be used, but these variants could have combined effect. The VCEP does not use this code.
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 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 with SpliceAI ≤ 0.1 Strong criteria applies to: Missense variants: REVEL between 0.004 and 0.016 with SpliceAI ≤ 0.1 Modification Type: General recommendation Moderate Applies to: Missense variants: REVEL between 0.017 and 0.183 with SpliceAI ≤ 0.1 Modification Type: General recommendation Supporting Applies to: Missense variants: REVEL between 0.184 and 0.290 with SpliceAI ≤ 0.1 or 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. VCEP Specifications: This code may be used with BP4 as described in the RS1-specific PVS1 Decision Tree file splicing document and Walker, et al, 2023. Stand Alone Very Strong Strong Applies to splicing assay data demonstrating a variant is not associated with aberrantly spliced transcript(s) relative to transcript profiles in controls. See RS1 PVS1 Decision Tree. As per Walker et al, 2023 (PMID 37352859) guidance. Modification Type: General recommendation,Gene-specific Moderate Supporting Applies to: Synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.1) AND PhyloP < 0.1 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, PS3, PS4, PM1_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, PM1, PM4, PM5, 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, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND 1 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong, PP3_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong, PP3_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong, PP3_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong, PP3_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_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, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM1_Strong, PP1_Strong, PP3_Strong) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP3, PP4)

Benign

≥ 2 Strong (BS1, BS2, BP4_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BP4_Strong) AND 1 Supporting (BS4_Supporting, BP4, BP7)

≥ 2 Supporting (BS4_Supporting, BP4, BP7)

Files & Images

RS1 PS2/PM6 Tables: OTC data for a proband showing schisis increases the available points.

RS1 PVS1 Decision Tree: PDF file of PVS1 Decision Tree for RS1 with splicing information.

RS1 Functional Evidence Assays for PS3 / BS3: Excel file of published functional assays, publications , and if they have been approved for use by the VCEP. Check the Approved row before use of any publication for a particular assay. 01/01/2025

References

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11. Heymann JB Vijayasarathy C et al. Cryo-EM of retinoschisin branched networks suggests an intercellular adhesive scaffold in the retina. J Cell Biol (2019) 218 (3) p. 1027-1038. 10.1083/jcb.201806148 30630865

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14. 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

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