ClinVar Genomic variation as it relates to human health

A Homozygote Missense variant c.392C>T in Exon 5 of the SLC26A3 gene that results in the amino acid substitution p.Pro131Leu was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic (variant ID: 56000). This variant was reported among the patients for Congenital chloride diarrhea (Wedenoja S et al., 2011). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Variant summary: SLC26A3 c.392C>T (p.Pro131Leu) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) 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 1.2e-05 in 251430 control chromosomes, predominantly at a frequency of 2.6e-05 within the Non-Finnish European subpopulation in the gnomAD database. c.392C>T has been reported in the literature in individuals affected with Congenital secretory diarrhea (example, Hong_2012, Fuwa_2015, Wedenoja_2011). These data indicate that the variant may be associated with disease. At-least one missense at Pro131 has been associated with disease in ClinVar (c.392C>G p.Pro131Arg: PATH/ClinVar, PMID 31114672). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 25711268, 23274434, 21394828). ClinVar contains an entry for this variant (Variation ID: 56000). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This missense change has been observed in individual(s) with congenital secretory chloride diarrhea (PMID: 23274434, 25711268). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 131 of the SLC26A3 protein (p.Pro131Leu). This variant is present in population databases (rs386833481, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 56000). 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 SLC26A3 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

Converted during submission to Likely pathogenic.