ClinVar

Description

The p.Ala253GlnfsX27 variant in SORD has been reported in European, East Asian, and Egyptian individuals with clinical diagnoses of Charcot-Marie-Tooth disease 2 or distal hereditary neuropathy, all of whom were homozygous or also carried a second SORD variant. This variant also segregated with disease in 7 affected individuals from 6 families (Cortese 2020, PMID: 32367058; Dong 2021, PMID: 33397963). The p.Ala253GlnfsX27 variant has been identified in 0.06% (15/24486) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has also been reported in ClinVar (Variation ID: 929258). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 253 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SORD gene is strongly associated with autosomal recessive sorbitol dehydrogenase deficiency with peripheral neuropathy. In vitro functional studies support an impact on protein function (Cortese 2020, PMID: 32367058; Dong 2021, PMID: 33397963). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive sorbitol dehydrogenase deficiency with peripheral neuropathy. ACMG/AMP Criteria applied: PVS1_Strong, PP1_Strong, PM3, PS3_Moderate.