rs267606686
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_033409.4(SLC52A3):c.106G>A(p.Glu36Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,998 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). Synonymous variant affecting the same amino acid position (i.e. E36E) has been classified as Likely benign.
Frequency
Consequence
NM_033409.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC52A3 | NM_033409.4 | c.106G>A | p.Glu36Lys | missense_variant | 2/5 | ENST00000645534.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC52A3 | ENST00000645534.1 | c.106G>A | p.Glu36Lys | missense_variant | 2/5 | NM_033409.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151958Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247354Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 133736
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1461040Hom.: 0 Cov.: 37 AF XY: 0.0000427 AC XY: 31AN XY: 726696
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151958Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74204
ClinVar
Submissions by phenotype
Brown-Vialetto-van Laere syndrome 1 Pathogenic:1Uncertain:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 36 of the SLC52A3 protein (p.Glu36Lys). This variant is present in population databases (rs267606686, gnomAD 0.003%). This missense change has been observed in individual(s) with Brown-Vialetto-Van Laere syndrome (BVVLS) (PMID: 20206331, 23688382, 29053833, 29950502). ClinVar contains an entry for this variant (Variation ID: 143). 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 SLC52A3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC52A3 function (PMID: 22273710). 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 12, 2010 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2021 | Identified in a patient with BVVLS who presented at 5 years old with sensorineural hearing loss, followed by speech difficulties, weakness, and respiratory issues; no second variant was identified (Malafronte et al., 2013); Published functional studies demonstrate reduced riboflavin uptake (Nabokina et al., 2012); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26072523, 22273710, 29950502, 23688382, 20206331, 23107375, 23506902, 29053833, 34662687) - |
Progressive bulbar palsy of childhood Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at