ClinVar Genomic variation as it relates to human health

Variant summary: SGSH c.1135delG (p.Val379CysfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250996 control chromosomes. c.1135delG has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Weber_1997, Chistiakov_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in the expression of a truncated protein that is degraded in the ER prior to sorting site in the Golgi (Muschol_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Val379Cysfs*34) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 124 amino acid(s) of the SGSH protein. This variant is present in population databases (rs777956287, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9285796, 15146460, 24875751). This variant is also known as delG1147 CCGT->CC-T. ClinVar contains an entry for this variant (Variation ID: 280988). For these reasons, this variant has been classified as Pathogenic.

SGSH: PM3:Strong, PVS1:Strong, PM2

The c.1135delG (p.Val379CysfsTer34) variant (also known as delG1147) results in a frameshift, and is predicted to result in premature termination of the protein. The p.Val379CysfsTer variant has been identified in at least six patients with mucopolysaccharidosis type III, including one in a homozygous state and five in a compound heterozygous state (Weber et al. 1997; Muschol et al. 2004; Chistiakov et al. 2014). Control data are unavailable for this variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Muschol et al. (2004) demonstrated that the p.Val379CysfsTer34 variant protein is degraded in the endoplasmic reticulum prior to the sorting site in the Golgi apparatus. In addition, Chistiakov et al. (2014) showed that the variant resulted in markedly reduced enzyme activity in patients compared to control levels. Patients who were compound heterozygous for the p.Val379CysfsTer34 variant and a common missense variant (p.Arg74Cys), had residual SGSH activity which was intermediate between the enzymatic activity in individuals who were homozygous for the p.Arg74Cys variant and those who were compound heterozygous for the p.Arg74Cys variant. Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.Val379CysfsTer34 variant is classified as pathogenic for mucopolysaccharidosis type III.