rs201799893
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_000343.4(SLC5A1):c.1673G>A(p.Arg558His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,610 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. R558C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000343.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC5A1 | NM_000343.4 | c.1673G>A | p.Arg558His | missense_variant | 14/15 | ENST00000266088.9 | |
SLC5A1 | NM_001256314.2 | c.1292G>A | p.Arg431His | missense_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC5A1 | ENST00000266088.9 | c.1673G>A | p.Arg558His | missense_variant | 14/15 | 1 | NM_000343.4 | P1 | |
SLC5A1 | ENST00000543737.2 | c.1292G>A | p.Arg431His | missense_variant | 13/14 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251244Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135774
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727090
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74252
ClinVar
Submissions by phenotype
Congenital glucose-galactose malabsorption Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 558 of the SLC5A1 protein (p.Arg558His). This variant is present in population databases (rs201799893, gnomAD 0.02%). This missense change has been observed in individual(s) with glucose-galactose malabsorption (PMID: 20486940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127077). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC5A1 protein function. This variant disrupts the p.Arg558 amino acid residue in SLC5A1. Other variant(s) that disrupt this residue have been observed in individuals with SLC5A1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 04, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 09, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at