Submissions for variant NM_003060.4(SLC22A5):c.934A>G (p.Ile312Val)

gnomAD frequency: 0.00085  dbSNP: rs77300588

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001311676	SCV000521561	likely benign	not provided	2021-04-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20574985, 18337137, 28841266)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540060	SCV000632578	likely benign	Renal carnitine transport defect	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000540060	SCV001317232	uncertain significance	Renal carnitine transport defect	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV001311676	SCV001501952	uncertain significance	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000540060	SCV002055761	likely benign	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000540060	SCV002576599	likely benign	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235209	SCV003934856	uncertain significance	not specified	2023-05-09	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.934A>G (p.Ile312Val) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 251494 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00085 vs 0.0046), allowing no conclusion about variant significance. c.934A>G has been reported in the literature as a VUS in the heterozygous state in individuals with cardiomyopathy suspected of Systemic Primary Carnitine Deficiency and as an uninformative genotype (i.e. zygosity not specified) in a case of sudden unexplained death (e.g. Amat di San Filippo_2008, Li_2010, Christiansen_2016). These reports do not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency. Publications reporting experimental evidence evaluating an impact on protein function found that the variant has little impact on carnitine transport, maintaining above 65% of WT activity (e.g. Amat di San Filippo_2008, Frigeni_2017). The following publications have been ascertained in the context of this evaluation (PMID: 18337137, 27650965, 28841266, 20574985). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as either likely benign (n=4) or VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001311676	SCV001929686	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001311676	SCV001976323	likely benign	not provided		no assertion criteria provided	clinical testing