ClinVar

Description

Variant summary: GAMT c.467C>A (p.Ala156Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-06 in 150994 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.467C>A, has been reported in the literature in an individual affected with a Leigh syndrome mimicking phenotype (i.e. neurodevelopmental delay) with symmetrical extrapyramidal lesions on MRI, in the absence of mitochondrial dysfunction (Stenton_2022), who also carried second GAMT missense variant (VUS). These data do not allow clear conclusions about variant significance. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated significantly reduced enzyme activity for the variant protein, however, the variant annotation in the study was somewhat dubious (Desroches_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.