Submissions for variant NM_003060.4(SLC22A5):c.287G>C (p.Gly96Ala)

gnomAD frequency: 0.00029  dbSNP: rs377767450

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022311	SCV000632545	likely benign	Renal carnitine transport defect	2025-01-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000859563	SCV001154513	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	SLC22A5: PM2, PS3:Supporting
Illumina Laboratory Services, Illumina	RCV000022311	SCV001313090	uncertain significance	Renal carnitine transport defect	2017-04-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260361	SCV001437306	uncertain significance	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.287G>C (p.Gly96Ala) 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 0.00041 in 195700 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00041 vs 0.0046), allowing no conclusion about variant significance. c.287G>C has been reported in the literature as a non-informative genotype (second allele not specified and/or reported as an unclassified variant) in settings of newborn screening for systemic primary carnitine deficiency (example, Li_2010, Frigeni_2017) and as a non-informative heterozygous genotype in a patient with a known pathogenic variant in SCN1A supporting the diagnosis of an SCN1A-related epilepsy (Dravet syndrome) (Vasta_2012). These data do not allow any conclusion about variant significance. At least two publications report conflicting experimental evidence on Carnitine transport/uptake assays depending upon the cell lines utilized (example, Frigeni_2017, Koleske_2022). The most pronounced variant effect results in approximately 20% of normal transport activity in a CHO-cell based system whereas a fully functional Carnitine uptake activity in a HEK-293 cell based system (Koleske_2022). The following publications have been ascertained in the context of this evaluation (PMID: 28841266, 36343260, 20574985, 26828774, 22494076). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LP, n=1; LB, n=1; VUS, n=3). Based on the conflicting lines of evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000022311	SCV002055740	uncertain significance	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000022311	SCV002576668	uncertain significance	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000859563	SCV005411860	uncertain significance	not provided	2023-07-31	criteria provided, single submitter	clinical testing	BS1, PS4_moderate