ClinVar

Description

Variant summary: HCFC1 c.3734C>G (p.Ser1245Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 189,199 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database , including 6 hemizygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in HCFC1 causing Methylmalonic Acidemia With Homocystinuria phenotype (0.00035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.3734C>G, has been reported in a patient affected with epilepsy, however without providing strong evidence for causality (He_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Methylmalonic Acidemia With Homocystinuria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37264743). ClinVar contains an entry for this variant (Variation ID: 2730954). Based on the evidence outlined above, the variant was classified as likely benign.