rs267607052
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_003060.4(SLC22A5):c.43G>T(p.Gly15Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,613,298 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G15E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003060.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.43G>T | p.Gly15Trp | missense_variant | 1/10 | ENST00000245407.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.43G>T | p.Gly15Trp | missense_variant | 1/10 | 1 | NM_003060.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000963 AC: 24AN: 249200Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135286
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1460994Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 726856
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152304Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74484
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:11
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | in vitro;research | Giacomini Lab, University of California, San Francisco | Oct 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 15 of the SLC22A5 protein (p.Gly15Trp). This variant is present in population databases (rs267607052, gnomAD 0.08%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20027113, 20574985, 21922592). ClinVar contains an entry for this variant (Variation ID: 6429). 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 SLC22A5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 21922592). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 28, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2017 | Variant summary: The SLC22A5 c.43G>T (p.Gly15Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 12/116676 control chromosomes at a frequency of 0.0001028, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC22A5 variant (0.0045644). This variant has been reported in many patients both as homozygotes and compound heterozygote. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 14, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.43G>T (p.Gly15Trp) in SLC22A5 gene has been reported in many patients both as homozygotes and compound heterozygote (Li FY et.al.,2010). Experimental studies have shown that this missense change affects SLC22A5 function (Rose EC et.al.,2012). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Gly15Trp variant is reported with allele frequency of 0.009% in gnomAD exomes and novel in 1000 Genomes. The amino acid Gly at position 15 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant the molecular diagnosis is not confirmed. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21922592, 26828774, 28841266, 20027113, 20574985, 21126579, 28711408) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at