ClinVar Genomic variation as it relates to human health

The Arg529Trp missense change in the SH3TC2 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. Two other amino acid substitutions at this same position (Arg529Cys and Arg529Gln) have been previously reported in association with CMT4C according to the Human Gene Mutation database. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged, non-polar Tryptophan residue at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, Arg529Trp is a strong candidate for a pathogenic variant, although the possibility that it is a benign variant cannot be excluded.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 529 of the SH3TC2 protein (p.Arg529Cys). This variant is present in population databases (rs750529207, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SH3TC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418488). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Arg529 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14574644, 19744956, 23281072; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant summary: SH3TC2 c.1585C>T (p.Arg529Cys) 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 2.8e-05 in 251308 control chromosomes in the gnomAD database, however in all individuals it was found as a multinucleotide variant in cis with c.1587T>G, which is expected to result in a different amino acid change (p.Arg529Trp). c.1585C>T has been reported in the literature in the homozygous state in individuals affected with and/or with clinical features of Charcot-Marie Disease Type 4C (CMT4C), where the amino acid change was reported as p.Arg529Cys, although the presence/absence of c.1587T>G in cis was not explicitly stated (Kingston_2012, Ek_2023). Additionally, it has also been found in cis with c.1587T>G in two compound heterozygous CMT4C patients who had a pathogenic variant in trans (Arntzen_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different variant affecting the same codon has been classified as pathogenic (c.1586_1587delinsAG, p.Arg529Gln), supporting the critical relevance of codon 529 to SH3TC2 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30001926, 37273706). ClinVar contains an entry for this variant (Variation ID: 418488). Based on the evidence outlined above, the variant was classified as likely pathogenic.