ClinVar

Description

The homozygous p.Ala633ProfsTer12 variant in SH3TC2 was identified by our study in two different families with Charcot-Marie-Tooth disease type 4C, one consisting of two affected siblings and the other consisting of three affected siblings, and segregated with disease in both of these families. The p.Ala633ProfsTer12 variant in SH3TC2 has been previously reported in one individual with Charcot-Marie-Tooth disease type 4C (PMID: 36790232). This affected individual (PMID: 36790232) and the three affected individuals from one of the families identified by our study were homozygotes, which increases the likelihood that the p.Ala633ProfsTer12 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 425358) and has been interpreted as pathogenic by the CMT Laboratory,Bogazici University and the Institute of Human Genetics, Klinikum rechts der Isar and as likely pathogenic by CeGaT Center for Human Genetics Tuebingen. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 633 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SH3TC2 gene is an established disease mechanism in autosomal recessive Charcot-Marie-Tooth disease type 4C. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Charcot-Marie-Tooth disease type 4C. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3, PP1 (Richards 2015).