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.

For general information about the ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding content correction or adding a new criteria specification refer to the Help page.

Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know by contacting us via email.

Criteria Specification

ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 2.1

Type: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 Description : Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel ACMG Classification Rules Specified for Solute Carrier Family 6, Member 8 (SLC6A8; Creatine Transporter) Summary of ACMG-AMP Criteria for SLC6A8 Variants. General: variant curation for SLC6A8 uses the Bayesian point-based approach as described by Tavtigian, 2020 (PMID: 32720330). See "Bayesian points system" attachment and disregard "Rules for Combining Criteria" at the end of this document.

Version : 2.1 DOI : 10.5281/zenodo.21421641 Release Notes :

Removed the attached document with the response to the SVI.

Cerebral Creatine Deficiency Syndromes VCEP

Released

7/6/2026

12:41:05

Contributors & Keywords

Research Group: Cerebral Creatine Deficiency Syndromes VCEP Rights Holder: The Clinical Genome Resource (ClinGen)

Keywords: human biology genomics variant variant classification clingen disease standards SLC6A8 NM_005629.4 X-linked inheritance creatine transporter deficiency

Rules for SLC6A8

Gene: SLC6A8 (HGNC:11055) HGNC Name: solute carrier family 6 member 8 Transcripts: NM_005629.4 Disease: creatine transporter deficiency (MONDO:0010305) 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 See attached PVS1 decision tree, adapted from Tayoun, et.al. 2018 [PMID:30192042] for nonsense, frameshift, predictions for canonical splice variants, deletions, duplications and initiation codon variants. See attached PVS1 decision tree, adapted from Walker, et. al. 2023 [PMID:37352859] for observed RNA splicing defects from functional splicing assays (minigene assay, RNA Sequencing, transcriptome analysis, etc) [PMID: 39418753] Default Point Value: 8 Modification Type: Gene-specific Strong See attached PVS1 decision tree, adapted from Tayoun, et.al. 2018 [PMID:30192042] for nonsense, frameshift, predictions for canonical splice variants, deletions, duplications and initiation codon variants. See attached PVS1 decision tree, adapted from Walker, et. al. 2023 [PMID:37352859] for observed RNA splicing defects from functional splicing assays (minigene assay, RNA Sequencing, transcriptome analysis, etc) [PMID: 39418753] Default Point Value: 4 Modification Type: Gene-specific Moderate See attached PVS1 decision tree, adapted from Tayoun, et.al. 2018 [PMID:30192042] for nonsense, frameshift, predictions for canonical splice variants, deletions, duplications and initiation codon variants. See attached PVS1 decision tree, adapted from Walker, et. al. 2023 [PMID:37352859] for observed RNA splicing defects from functional splicing assays (minigene assay, RNA Sequencing, transcriptome analysis, etc) [PMID: 39418753] Default Point Value: 2 Modification Type: Gene-specific Supporting See attached PVS1 decision tree, adapted from Tayoun, et.al. 2018 [PMID:30192042] for nonsense, frameshift, predictions for canonical splice variants, deletions, duplications and initiation codon variants. See attached PVS1 decision tree, adapted from Walker, et. al. 2023 [PMID:37352859] for observed RNA splicing defects from functional splicing assays (minigene assay, RNA Sequencing, transcriptome analysis, etc) [PMID: 39418753] Default Point Value: 1 Modification Type: Gene-specific 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. Stand Alone Very Strong Strong PS1 is applicable as described. PS1 may also be applicable for intronic variants in the canonical splice consensus sequence or in the splice region. See “PS1_SpliceVariants” for applicable points, from Walker, et.al. PMID:37352859 Splice AI score must be <0.1 for both the variant under review and the previously reported variant to apply this code. Default Point Value: 4 Modification Type: General recommendation Moderate PS1 is applicable as described PS1_Moderate may also be applicable for intronic variants in the canonical splice consensus sequence or in the splice region. See “PS1_SpliceVariants” for applicable points Default Point Value: 2 Modification Type: General recommendation Supporting PS1 is applicable as described PS1_Supp may also be applicable for intronic variants in the canonical splice consensus sequence or in the splice region. See “PS1_SpliceVariants” for applicable points Default Point Value: 1 Modification Type: 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. Stand Alone Very Strong Default Point Value: 8 Strong Is applicable in the case of a hemizygous male or a heterozygous female minimally meeting PP4_Supporting with a de novo variant confirmation of maternity only is sufficient in male probands confirmation of both maternity and paternity is necessary in female probands Default Point Value: 4 Modification Type: Disease-specific,None Moderate Is applicable in the case of a newly hemizygous male with variant identified de novo in asymptomatic mother when one of the following conditions are met Identified in male proband minimally meeting PP4_Supporting if the biological mother (asymptomatic or affected) has a de novo SLC6A8 variant confirmed by parental testing in her parents Identified in male proband minimally meeting PP4_Supporting if the biological mother (asymptomatic or affected) has a mosaic SLC6A8 (≤30% variant allele frequency) Default Point Value: 2 Modification Type: Disease-specific,Strength Supporting Default Point Value: 1 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: Variants demonstrated by functional assays to alter splicing should not be scored under PS3 criteria. Please see PVS1 (above) and PVS1 decision tree (attached) to apply appropriate strength for variants with functional splicing data. Decision tree for variants with observed RNA splicing defects adapted from Walker, et.al 2023 [PMID:37352859]. Stand Alone Very Strong Default Point Value: 8 Strong Default Point Value: 4 Moderate Creatine transport deficient mouse models have biochemical findings including reduced/absent creatine in brain [PMID:21249153, 25485098, 33389772], which has been recapitulated in brain-specific creatine transport knockout models [PMID:22751104]. PS3_Moderate is applicable when the variant under review is used to generate a mouse knock-in model and assessment of brain creatine demonstrates significantly reduced or absent brain creatine when compared to wildtype littermates. Default Point Value: 2 Modification Type: Gene-specific Supporting Creatine transport assay using site directed mutagenesis to introduce the variant under review into SLC6A8 deficient cell line, and results in <10% creatine transport compared to wildtype cells when using ≤125uM creatine, or ≤25% when using creatine >125uM. Default Point Value: 1 Modification Type: Disease-specific,Strength Not 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 1: Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article 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. Note 3: A single individual cannot be counted for both PP4 and PS4. Use the individual with the highest possible PP4 evidence under that code and use PS4 to count additional affected individuals. Stand Alone Very Strong 8 independent probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4. Affected females may be counted if meeting PP4_Supporting Variant must meet PM2_Supporting criterion for PS4 to apply. Default Point Value: 8 Modification Type: Gene-specific,Strength Strong 4 independent probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4. Affected females may be counted if meeting PP4_Supporting Variant must meet PM2_Supporting criterion for PS4 to apply. Default Point Value: 4 Modification Type: Disease-specific Moderate 2 independent probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4. Affected females may be counted if meeting PP4_Supporting Variant must meet PM2_Supporting criterion for PS4 to apply. Default Point Value: 2 Modification Type: Strength Supporting 1 independent proband with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4. Variant must meet PM2_Supporting criterion for PS4 to apply. Default Point Value: 1 Modification Type: 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 Default Point Value: 4 Moderate Default Point Value: 2 Supporting Default Point Value: 1 Not Applicable Comments: Not applicable
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. VCEP Specifications: PM2 at Moderate strength level is not applicable per SVI recommendations Stand Alone Very Strong Strong Moderate Default Point Value: 2 Supporting Applicable when Grpmax Filtering Allele Frequency is ≤0.00002 (0.002%) AND 0 homo- or hemizygotes are present in the most current version of gnomAD available at the time of curation Default Point Value: 1 Modification Type: Disease-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 Default Point Value: 8 Strong Default Point Value: 4 Moderate Default Point Value: 2 Supporting Default Point Value: 1 Not Applicable Comments: SLC6A8 is an X-linked gene, therefore PM3 is 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. Stand Alone Very Strong Strong Default Point Value: 4 Moderate Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants. Default Point Value: 2 Modification Type: None Supporting Default Point Value: 1 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 Default Point Value: 4 Moderate Same as described. Splice AI score must be <0.1 for both the variant under review and the previously reported variant to apply this code. Default Point Value: 2 Modification Type: Gene-specific Supporting Novel missense change at an amino acid residue where a different missense change determined to be Likely pathogenic has been seen before. Example: Arg156His is Likely pathogenic; now you observe Arg156Cys Default Point Value: 1 Modification Type: Strength 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. Stand Alone Very Strong Default Point Value: 8 Strong Default Point Value: 4 Moderate See criteria in PS2. Default Point Value: 2 Modification Type: No change Supporting Default Point Value: 1 Not Applicable
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: Based on Biesecker, 2024 [PMID:38103548], the following strength levels are applicable for SLC6A8 – segregations include: variant positive, phenotype positive males variant negative, phenotype negative males variant positive, phenotype positive females variant positive asymptomatic females should NOT be counted Total locus evidence for PP1+PP4 must be capped at 5.0 points per allele Stand Alone Very Strong Strong 4 segregations Default Point Value: 4 Modification Type: Strength Moderate 2 segregations Default Point Value: 2 Modification Type: Strength Supporting 1 segregations Default Point Value: 1 Modification Type: Disease-specific 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 Default Point Value: 1 Not Applicable Comments: Not applicable, Missense Z score is 3.05 (o/e =0.46).
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 Default Point Value: 4 Moderate Default Point Value: 2 Supporting Applicable for missense variants with REVEL >0.75 Applicable for canonical splice, splice region, or deep intronic variants with SpliceAI delta score ≥0.20 Default Point Value: 1 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: See attached PP4 table for phenotypes in males and/or female probands required to meet PP4 criteria. Point total for applicable PP4 criteria should be summed. • Sum of points for phenotype from attached table and strength at which to apply PP4 PP4 (+1): = 1-2 points PP4_Moderate (+2): = 3 points PP4_Strong (+4): = 4 points Stand Alone Very Strong Strong See attached PP4 table for phenotypes in males and/or female probands required to meet PP4 criteria. Point total for applicable PP4 criteria should be summed. PP4_Strong (+4): = 4 points Two or more data types are required to reach strong. An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4. Variant must meet PM2_Supporting for PP4 to apply at any strength. For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries must have been carried out. If not, downgrade by one strength level. Total locus evidence for PP1+PP4 must be capped at 5.0 points per allele Default Point Value: 4 Modification Type: Disease-specific Moderate See attached PP4 table for phenotypes in males and/or female probands required to meet PP4 criteria. Point total for applicable PP4 criteria should be summed. PP4_Moderate (+2): = 3 points An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4. Variant must meet PM2_Supporting for PP4 to apply at any strength. Total locus evidence for PP1+PP4 must be capped at 5.0 points per allele Default Point Value: 2 Modification Type: Strength Supporting See attached PP4 table for phenotypes in males and/or female probands required to meet PP4 criteria. Point total for applicable PP4 criteria should be summed. PP4 (+1): = 1-2 points An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4. Variant must meet PM2_Supporting for PP4 to apply at any strength. Total locus evidence for PP1+PP4 must be capped at 5.0 points per allele Default Point Value: 1 Modification Type: Disease-specific 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 Applicable when Grpmax Filtering Allele Frequency is ≥0.002 (0.2%) OR ≥10 homo- or hemizygotes (or the sum of total hemi- and homozygotes) are present in the most current version of gnomAD available at the time of curation. Default Point Value: Not Applicable Modification Type: Disease-specific 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 Applicable when Grpmax Filtering Allele Frequency is ≥0.0002 (0.02%) Default Point Value: -4 Modification Type: Disease-specific Moderate Default Point Value: -2 Supporting Default Point Value: -1 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 Applicable when the variant is observed in ≥2 homo- or hemizygotes in the most current version of gnomAD available at the time of curation OR the variant is identified in a male with documented normal urine creatine/creatinine ratio BS1 and BS2 should not be co-applied based on the number of homo- or hemizygotes present in gnomAD Default Point Value: -4 Modification Type: Gene-specific Moderate Default Point Value: -2 Supporting Can be used if the variant is identified in a male with creatine transport studies ≥80% compared to wildtype if ≤125uM creatine was used in the study. Default Point Value: -1 Modification Type: Gene-specific 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. VCEP Specifications: BS3 is not applicable at Strong strength level Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Creatine transport assay demonstrating ≥50% normal transport activity compared to controls when using ≤125uM creatine. Any study using >125uM creatine for creatine transporter assays cannot be used as Benign evidence. RT-PCR evidence demonstrating no observable effect of splicing for canonical splice, splice region, and deep intronic variants Expression assay demonstrating wildtype transcript levels Default Point Value: -1 Modification Type: Disease-specific,Strength 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 Asymptomatic, variant positive females should NOT be used as benign segregation evidence Default Point Value: -4 Modification Type: None Moderate Default Point Value: -2 Supporting Default Point Value: -1 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 Default Point Value: -4 Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable Comments: Not applicable, truncating and missense variants have been reported in affected patients.
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 Default Point Value: -4 Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable Comments: Not applicable, SLC6A8 is an 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 Default Point Value: -4 Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable Comments: Not applicable, SLC6A8 is a transmembrane protein with no repetitive regions of unknown function.
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 Default Point Value: -4 Moderate Default Point Value: -2 Supporting REVEL score ≤ 0.20 For variants potentially impacting splicing, Splice AI score <0.10 Default Point Value: -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 Default Point Value: -4 Moderate Default Point Value: -2 Supporting Use as described. Default Point Value: -1 Modification Type: None 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 Default Point Value: -4 Moderate Default Point Value: -2 Supporting A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site SpliceAI score ≤0.10 May also be applied in conjunction with PB4 for an intronic variant outside the splice region (beyond -4bp or +7 bp) Default Point Value: -1 Modification Type: Gene-specific Not Applicable

Point Based Variant Classification Categories

Category	Point Ranges
Pathogenic	10
Likely Pathogenic	6 - 9
Uncertain Significance	-1 - 5
Likely Benign	-6 - -2
Benign	-7

Additional Notes :

Files & Images

SLC6A8 Functional Assay SVI documentation:

SLC6A8_PVS1_v2.1_033026:

SLC6A8 PP4 V2:

SLC6A8_Bayesian Points System_033026:

SLC6A8 PS1 Splice Variants: