ClinVar Genomic variation as it relates to human health

Variant summary: CTNS c.922G>A (p.Gly308Arg) results in a non-conservative amino acid change located in the sixth transmembrane domain (Kalatzis_2004) of 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 4e-06 in 251050 control chromosomes (gnomAD). c.922G>A has been reported in the literature in multiple individuals affected with Cystinosis (Shotelersuk_1998, Attard_1999). These data indicate that the variant is very likely to be associated with disease. At least two functional studies reports this variant is sufficient to abolish the transport activity of cystinosin without altering its subcellular localization. Two Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

ClinVar contains an entry for this variant (Variation ID: 267310). This missense change has been observed in individuals with cystinosis (PMID: 9792862, 12204010, 15128704, 19863563, 26266097). This variant is present in population databases (rs746307931, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 308 of the CTNS protein (p.Gly308Arg). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTNS protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly308 amino acid residue in CTNS. Other variant(s) that disrupt this residue have been observed in individuals with CTNS-related conditions (PMID: 9792862, 12204010, 23640116), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects CTNS function (PMID: 11689434, 12204010).

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000267310, PMID:9792862,28793998). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 19863563, 26266097). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12204010). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:23640116,12204010). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.991>=0.6, 3CNET: 0.972>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). herefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.