Submissions for variant NM_003060.4(SLC22A5):c.1411C>T (p.Arg471Cys)

gnomAD frequency: 0.00001  dbSNP: rs749282641

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535447	SCV000632529	pathogenic	Renal carnitine transport defect	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 471 of the SLC22A5 protein (p.Arg471Cys). This variant is present in population databases (rs749282641, gnomAD 0.007%). This missense change has been observed in individual(s) with primary systemic carnitine deficiency and an associated short QT syndrome, and carnitine update defect (PMID: 20074989, 26190315). 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: 460398). 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%. This variant disrupts the p.Arg471 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14605509, 16652335, 25132046; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001546222	SCV001765705	pathogenic	not provided	2020-12-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26190315, 20074989, 23520115, 26828774, 29132460)
Genome-Nilou Lab	RCV000535447	SCV002055831	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000535447	SCV002576658	likely pathogenic	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000535447	SCV004020910	pathogenic	Renal carnitine transport defect	2023-06-13	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1411C>T (p.Arg471Cys) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of 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 8e-06 in 251428 control chromosomes. c.1411C>T has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Example: Chen_2013, Chen_2021, Lee_2010, Roussel_2016, Tan_2021). These data indicate that the variant is likely to be associated with disease. Other variants affecting the same amino acid have been classified as pathogenic/likely pathogenic in ClinVar (p.Arg471Pro, p.Arg471Ser, p.Arg471His), this data suggests a critical role for this amino acid in 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: 23520115, 33560599, 36343260, 20074989, 26190315, 34394177). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000535447	SCV004201309	pathogenic	Renal carnitine transport defect	2023-06-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV002226469	SCV002078357	pathogenic	Decreased circulating carnitine concentration	2021-09-30	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000535447	SCV002107479	pathogenic	Renal carnitine transport defect	2021-09-30	no assertion criteria provided	clinical testing