Submissions for variant NM_003060.4(SLC22A5):c.371A>G (p.Tyr124Cys)

gnomAD frequency: 0.00001  dbSNP: rs762126547

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000998437	SCV001154514	likely pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV001051306	SCV001215452	uncertain significance	Renal carnitine transport defect	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 124 of the SLC22A5 protein (p.Tyr124Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of primary carnitine deficiency (PMID: 32371215). ClinVar contains an entry for this variant (Variation ID: 809800). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001051306	SCV002055742	uncertain significance	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV001051306	SCV002576663	uncertain significance	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987757	SCV004803266	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.371A>G (p.Tyr124Cys) 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 8.3e-06 in 239790 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.371A>G has been reported in the literature in at least one compound heterozygous individual affected with Primary Carnitine Deficiency (e.g., Lin_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in an approximately 80% reduction in carnitine transport function relative to the wild-type protein (e.g., Koleske_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36343260, 32371215). ClinVar contains an entry for this variant (Variation ID: 809800). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV002226506	SCV002078301	uncertain significance	Decreased circulating carnitine concentration	2020-07-08	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001051306	SCV002107424	uncertain significance	Renal carnitine transport defect	2020-07-08	no assertion criteria provided	clinical testing