Submissions for variant NM_003060.4(SLC22A5):c.1354G>A (p.Glu452Lys)

gnomAD frequency: 0.00001  dbSNP: rs72552734

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153964	SCV000203584	uncertain significance	not provided	2015-06-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000022377	SCV000220160	likely pathogenic	Renal carnitine transport defect	2014-03-13	criteria provided, single submitter	literature only
Invitae	RCV000022377	SCV000817118	pathogenic	Renal carnitine transport defect	2024-01-30	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022377	SCV001431936	pathogenic	Renal carnitine transport defect	2020-08-07	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV000022377	SCV002055773	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000153964	SCV002545350	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	SLC22A5: PP4:Strong, PM2, PM3, PP3, PS3:Supporting
Baylor Genetics	RCV000022377	SCV004201291	likely pathogenic	Renal carnitine transport defect	2024-02-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000022377	SCV001462822	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing