ClinVar Genomic variation as it relates to human health

The SLC26A2 c.1650delG (p.Ser551ValfsTer34) variant, which is also reported as c.1677delG, results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser551ValfsTer34 variant was reported in a single study in which it was found in one individual with diastrophic dysplasia, although zygosity information was not provided (Rossi et al. 2001). The p.Ser551ValfsTer34 variant was absent from 100 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on a single allele in a region of good sequence coverage, so the variant is presumed to be rare. Due to the potential impact of frameshift variants and the lack of clarifying evidence, the p.Ser551ValfsTer34 variant is classified as a variant of unknown significance but suspicious for pathogenicity for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Frameshift variant predicted to result in protein truncation, as the last 189 amino acids are replaced with 33 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Identified in a patient with diastrophic dysplasia in the published literature (Rossi et al., 2001); This variant is associated with the following publications: (PMID: 11241838)

Variant summary: SLC26A2 c.1650delG (p.Ser551ValfsX34) 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. Truncations downstream of this position have been associated with Disatrophic Dysplasia in HGMD. The variant allele was found at a frequency of 8e-06 in 250808 control chromosomes. c.1650delG has been reported in the literature in individual(s) affected with Diastrophic Dysplasia (Rossi_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as: Pathogenic (n=1), Likely Pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change creates a premature translational stop signal (p.Ser551Valfs*34) in the SLC26A2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 189 amino acid(s) of the SLC26A2 protein. This variant is present in population databases (rs386833497, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of SLC26A2-related conditions (PMID: 11241838). ClinVar contains an entry for this variant (Variation ID: 56016). This variant disrupts a region of the SLC26A2 protein in which other variant(s) (p.Glu703Glyfs*9) 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. For these reasons, this variant has been classified as Pathogenic.

Converted during submission to Likely pathogenic.

The SLC26A2 c.1650delG variant is predicted to result in a frameshift and premature protein termination (p.Ser551Valfs*34). This variant along with a second variant in this gene has been reported in at least one individual with diastrophic dysplasia (Paganini et al. 2023. PubMed ID: 37454964). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in SLC26A2 are expected to be pathogenic. This variant is interpreted as pathogenic.