ClinVar

Description

The NM_000156.6:c.507_521dup (p.Cys169_Ser173dup) variant in GAMT is a protein length-changing variant (in-frame insertion) in a non-repeat region (PM4). This variant has been previously reported in at least two cases with clinical symptoms consistent with GAMT deficiency. One proband had elevated plasma GAA and was compound heterozygous for the variant and a pathogenic variant in GAMT, c.327G>A (p.Lys109=), with the variants confirmed in trans by parental testing (PMID: 23583224, 29506905; personal communication). Another proband had elevated plasma GAA and reduced cerebral creatine by MRS, pretreatment, and was compound heterozygous for the variant and c.403G>T (p.Asp135Tyr) (PMID: 19027335, 23660394) (PP4_Strong, PM3). The allelic data for the latter patient will be used in the classification of p.Asp135Tyr and was not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00000883 (1/113306 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictors PROVEAN and MutPred-Indel gave scores consistent with a damaging effect on GAMT function, but MutationTaster suggested no impact (PP3 was not applied). There is a ClinVar entry for this variant (Variation ID: 431959). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_strong, PM3, PM2_supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).