Submissions for variant NM_003060.4(SLC22A5):c.396G>A (p.Trp132Ter)

gnomAD frequency: 0.00001  dbSNP: rs72552727

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000006780	SCV000220445	likely pathogenic	Renal carnitine transport defect	2014-06-22	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006780	SCV000833822	pathogenic	Renal carnitine transport defect	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp132*) in the SLC22A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs72552727, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary carnitine deficiency (PMID: 9916797, 19208393). ClinVar contains an entry for this variant (Variation ID: 6411). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000006780	SCV002055801	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006780	SCV002598743	pathogenic	Renal carnitine transport defect	2022-09-14	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.396G>A (p.Trp132X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and associated with phenotype in HGMD. The variant allele was found at a frequency of 8e-06 in 251496 control chromosomes. c.396G>A has been reported in the literature in multiple individuals with clinically diagnosed Systemic Primary Carnitine Deficiency (example, Koizumi_1999, Nezu_1999 and Ohkuma 2009 etc.). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000006780	SCV004201259	pathogenic	Renal carnitine transport defect	2023-12-26	criteria provided, single submitter	clinical testing
GeneDx	RCV004589498	SCV005080743	pathogenic	not provided	2023-12-07	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect (significantly reduced carnitine uptake activity compared to wild-type) (PMID: 10072434); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25846890, 19208393, 9916797, 34394177, 26828774, 34997761, 33560599, 29869463, 36568374, 29111448, 29519241, 31364285, 20574985, 10545605, 28841266, 28164076, 32371215, 10072434)
Fulgent Genetics, Fulgent Genetics	RCV000006780	SCV005669194	pathogenic	Renal carnitine transport defect	2024-06-08	criteria provided, single submitter	clinical testing
OMIM	RCV000006780	SCV000026976	pathogenic	Renal carnitine transport defect	1999-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000006780	SCV001458686	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing