ClinVar Genomic variation as it relates to human health

PM2: gnomAD genomes East Asian allele frequency = 0.00005437<0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in two patients and phase unknown in four patients PM5: Another missense pathogenic variant (c.2168A>G, p.His723Arg) at the same codon PP3: REVEL score > 0.7 PP4: Patient's phenotype highly specific for gene

Variant summary: SLC26A4 c.2167C>G (p.His723Asp) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense variant is classified as pathogenic (p.His723Arg). 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 251304 control chromosomes (gnomAD). c.2167C>G has been reported in the literature in multiple individuals affected with non-syndromic deafness (Dai_2008. Yao_2015, Wu_2022, Tian_2021, Zhang_2019, Xiang_2019), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19040761, 26035154, 35249537, 34170635, 31107121, 31035178). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces histidine with aspartic acid at codon 723 of the SLC26A4 protein (p.His723Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with enlarged vestibular aqueduct (PMID: 19040761, 22289209, 25372295, 26035154). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.His723 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11405873, 20583162, 22884721, 23755160, 24338212). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.