rs727504159
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_003060.4(SLC22A5):c.338G>A(p.Cys113Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,524 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).
Frequency
Consequence
NM_003060.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.338G>A | p.Cys113Tyr | missense_variant | 1/10 | ENST00000245407.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.338G>A | p.Cys113Tyr | missense_variant | 1/10 | 1 | NM_003060.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152262Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000125 AC: 3AN: 239782Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130944
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459144Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 725722
GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152380Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74514
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:6Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2023 | Variant summary: SLC22A5 c.338G>A (p.Cys113Tyr) results in a non-conservative amino acid change in 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 1.3e-05 in 239782 control chromosomes. c.338G>A has been reported in the literature as biallelic genotypes in multiple individuals affected with Systemic Primary Carnitine Deficiency (example, Han_2014, Tan_2021, Zhang_2019). These data indicate that the variant is very 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: 25132046, 34394177, 31364285). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Uncertain significance, criteria provided, single submitter | in vitro;research | Giacomini Lab, University of California, San Francisco | Oct 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 113 of the SLC22A5 protein (p.Cys113Tyr). This variant is present in population databases (rs727504159, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 25132046, 25224063). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167696). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 29, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Decreased circulating carnitine concentration Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 07, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 10, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at