ClinVar Genomic variation as it relates to human health

This mutation leads to frameshift mutation (p.A179R fs*141) and was found to be pathogenic by in silico tools. Parents were found to be heterozygous carriers.

The c.533dupG variant in the CHST3 gene has been reported previously in the homozygous state, using alternate nomenclature of c.533_534insG, in two unrelated Arab individuals affected with carbohydrate sulfotransferase 3 deficiency, congenital joint dislocations, and short stature (Unger et al., 2010). The same homozygous variant was also reported in a child of Indian descent with extreme short stature, joint contractures and prominence, and vertebral abnormalities (Srivastava et al., 2017). The c.533dupG variant causes a frameshift starting with codon Alanine 179, changes this amino acid to am Arginine residue, and creates a premature Stop codon at position 141 of the new reading frame, denoted p.Ala179ArgfsX141. This variant is predicted to cause loss of normal protein function through protein truncation. The c.533dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.533dupG as a likely pathogenic variant.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000432012). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CHST3 protein in which other variant(s) (p.Leu286Trpfs*48) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 432012). This premature translational stop signal has been observed in individuals with CHST3-related conditions (PMID: 20830804, 27753269; Invitae). This variant is present in population databases (rs774572727, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Ala179Argfs*141) in the CHST3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 301 amino acid(s) of the CHST3 protein.