rs72552734
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_003060.4(SLC22A5):c.1354G>A(p.Glu452Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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 Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.1354G>A | p.Glu452Lys | missense_variant | 8/10 | ENST00000245407.8 | NP_003051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.1354G>A | p.Glu452Lys | missense_variant | 8/10 | 1 | NM_003060.4 | ENSP00000245407 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251480Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461754Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727186
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Mar 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2020 | Variant summary: SLC22A5 c.1354G>A (p.Glu452Lys) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251480 control chromosomes. c.1354G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (example, Li_2010, Deswal_2017, Frigeni_2017, Wang_2000). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example Frigeni_2017, Wang_2000). The most pronounced variant effect results in <10% of normal carnitine transport activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories have recently classified/re-classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 452 of the SLC22A5 protein (p.Glu452Lys). This variant is present in population databases (rs72552734, gnomAD 0.01%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 10679939, 20574985, 27581592). ClinVar contains an entry for this variant (Variation ID: 25421). 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: 10679939). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2024 | Published functional studies demonstrate 24% of wild type transporter (PMID: 10679939); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 34637945, 28711408, 10679939, 15714519, 27581592, 16652335, 20574985, 28841266, 32778825, 35853679) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | SLC22A5: PP4:Strong, PM2, PM3, PP3, PS3:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at