rs386833480
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000111.3(SLC26A3):c.386C>T(p.Pro129Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P129R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000111.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A3 | NM_000111.3 | c.386C>T | p.Pro129Leu | missense_variant | 5/21 | ENST00000340010.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A3 | ENST00000340010.10 | c.386C>T | p.Pro129Leu | missense_variant | 5/21 | 1 | NM_000111.3 | P1 | |
SLC26A3 | ENST00000379083.7 | c.*177C>T | 3_prime_UTR_variant, NMD_transcript_variant | 5/20 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251422Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727210
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
Congenital secretory diarrhea, chloride type Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2023 | Variant summary: SLC26A3 c.386C>T (p.Pro129Leu) 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 8e-06 in 251422 control chromosomes (gnomAD). c.386C>T has been reported in the literature as a biallelic genotype in at least three individuals affected with Congenital secretory diarrhea, chloride type, including one case of a homozygous individual who also had a diagnosis of Cystic Fibrosis, however pseudo-Bartters syndrome was ruled out in favor of congenital chloride diarrhea following urine and electrolyte stool studies and genetic analysis (e.g. Wedenoja_2011, Canani_2013, Masip_2020, Heinz-Erian_2021 (no PMID)). These data indicate that the variant is likely to be associated with disease. 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: 24350656, 31976143, 21394828) Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and the other classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Sep 08, 2017 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 11, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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"). ClinVar contains an entry for this variant (Variation ID: 55998). This missense change has been observed in individual(s) with congenital chloride diarrhea (PMID: 21394828, 24350656). This variant is present in population databases (rs386833480, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 129 of the SLC26A3 protein (p.Pro129Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at