ClinVar

Description

Variant summary: AMPD1 c.34C>T (p.Gln12X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Most truncations downstream of this position have been classified as uncertain significance in ClinVar. The variant allele was found at a frequency of 0.086 in 251114 control chromosomes, predominantly at a frequency of 0.13 within the Non-Finnish European subpopulation in the gnomAD database, including 986 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in AMPD1 causing Muscle AMP Deaminase Deficiency phenotype (0.11), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.34C>T has been reported in the literature in multiple homozygous and heterozygous individuals affected with Muscle AMP Deaminase Deficiency (Morisaki_1992, Rannou_2017). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in decreasing normal AMPD activity (Morisaki_1992, Kalsi_2003, Rannou_2017). Seven ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=3), uncertain significance (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.