rs563607795
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_025243.4(SLC19A3):āc.1154T>Gā(p.Leu385Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,848 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. L385P) has been classified as Uncertain significance.
Frequency
Consequence
NM_025243.4 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 |
---|---|---|---|---|---|---|---|
SLC19A3 | NM_025243.4 | c.1154T>G | p.Leu385Arg | missense_variant | 4/6 | ENST00000644224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC19A3 | ENST00000644224.2 | c.1154T>G | p.Leu385Arg | missense_variant | 4/6 | NM_025243.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461848Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727230
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Biotin-responsive basal ganglia disease Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 19, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 385 of the SLC19A3 protein (p.Leu385Arg). This variant is present in population databases (rs563607795, gnomAD 0.003%). This missense change has been observed in individual(s) with SLC19A3-related conditions (PMID: 23482991). ClinVar contains an entry for this variant (Variation ID: 215161). 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 SLC19A3 protein function. 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, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The SLC19A3 c.1154T>G (p.Leu385Arg) variant has been reported in one study in which it is found in seven patients with an unidentified leukoencephalopathy including three patients in a homozygous state and four patients in a presumed compound heterozygous state (Kevelam et al. 2013). The variant was absent from 13,000 control chromosomes and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele in an area of good coverage so the variant is presumed to be rare. Based on the evidence, the p.Leu385Arg variant is classified as pathogenic for thiamine metabolism dysfunction syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at