Submissions for variant NM_003060.4(SLC22A5):c.1139C>T (p.Ala380Val)

gnomAD frequency: 0.00001  dbSNP: rs746187344

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669110	SCV000793822	uncertain significance	Renal carnitine transport defect	2017-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282306	SCV002572294	uncertain significance	not specified	2023-06-21	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1139C>T (p.Ala380Val) results in a non-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 251476 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1139C>T has been reported in the literature in reportedly asymptomatic cases in settings of newborn screening for Systemic Primary Carnitine Deficiency (e.g. Chen_2013, Line_2020, Lin_2021). These reports do not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency. 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: 23520115, 33181153, 32371215). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669110	SCV003439200	pathogenic	Renal carnitine transport defect	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 380 of the SLC22A5 protein (p.Ala380Val). This variant is present in population databases (rs746187344, gnomAD 0.01%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 23520115, 33757571). ClinVar contains an entry for this variant (Variation ID: 553624). 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.
Baylor Genetics	RCV000669110	SCV004201295	likely pathogenic	Renal carnitine transport defect	2023-08-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754525	SCV005359887	likely pathogenic	SLC22A5-related disorder	2024-07-12	no assertion criteria provided	clinical testing	The SLC22A5 c.1139C>T variant is predicted to result in the amino acid substitution p.Ala380Val. This variant has been reported in the compound heterozygous state in several individuals with biochemical features consistent with primary carnitine deficiency (see for example Chen et al 2013. PubMed ID: 23520115; Lin et al 2020. PubMed ID: 33181153). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. This variant has interpretations of uncertain significance (2), likely pathogenic (1), and pathogenic (1) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/553624/). This variant is interpreted as likely pathogenic.