Submissions for variant NM_000111.3(SLC26A3):c.392C>T (p.Pro131Leu)

dbSNP: rs386833481

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lifecell International Pvt. Ltd	RCV000049409	SCV003915934	pathogenic	Congenital secretory diarrhea, chloride type		criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003556127	SCV004295520	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 56000). 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 variant is present in population databases (rs386833481, gnomAD 0.003%). 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049409	SCV005381794	likely pathogenic	Congenital secretory diarrhea, chloride type	2024-08-26	criteria provided, single submitter	clinical testing	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.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049409	SCV000081842	probable-pathogenic	Congenital secretory diarrhea, chloride type		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.