Submissions for variant NM_003060.4(SLC22A5):c.338G>A (p.Cys113Tyr)

gnomAD frequency: 0.00001  dbSNP: rs727504159

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153959	SCV000203578	pathogenic	not provided	2014-01-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000411999	SCV000486718	likely pathogenic	Renal carnitine transport defect	2016-07-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411999	SCV000930783	pathogenic	Renal carnitine transport defect	2024-01-24	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV000411999	SCV002055798	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000411999	SCV002576644	uncertain significance	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411999	SCV004020908	pathogenic	Renal carnitine transport defect	2023-06-26	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000411999	SCV004201276	pathogenic	Renal carnitine transport defect	2024-03-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV002226458	SCV002078298	pathogenic	Decreased circulating carnitine concentration	2021-07-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000411999	SCV002107421	pathogenic	Renal carnitine transport defect	2021-07-07	no assertion criteria provided	clinical testing