Submissions for variant NM_003060.4(SLC22A5):c.760C>T (p.Arg254Ter)

dbSNP: rs121908893

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000490002	SCV000111954	pathogenic	not provided	2014-02-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000490002	SCV000576891	pathogenic	not provided	2018-11-02	criteria provided, single submitter	clinical testing	The R254X nonsense variant in the SLC22A5 gene has been reported previously in the homozygous and compound heterozygous states in association with primary/systemic carnitine deficiency, and is considered a founder mutation in the Chinese population (Tang et al., 2002; Hitomi et al., 2015). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R254X variant is observed in 13/8654 (0.15%) alleles from individuals of East Asian background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret R254X as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506929	SCV000605136	pathogenic	not specified	2017-04-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006795	SCV000698154	pathogenic	Renal carnitine transport defect	2016-12-30	criteria provided, single submitter	clinical testing	Variant summary: The SLC22A5 variant, c.760C>T (p.Arg254X) causes a nonsense mutation resulting in a predicted truncated protein, a known mechanism for decay. The variant of interest has been observed in controls with an allele frequency of 14/121906 (1/8710), which does not exceed the estimated maximum expected allele frequency for a pathogenic SLC22A5 variant of 1/219. Multiple publications cite the variant in homozygous affected individuals, which are indicated to have low carnitine levels. In addition, multiple databases/clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006795	SCV000820838	pathogenic	Renal carnitine transport defect	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg254*) 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 (rs121908893, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with primary carnitine deficiency (PMID: 12204000, 15303004, 17703373, 20208395, 26252091). ClinVar contains an entry for this variant (Variation ID: 6426). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000006795	SCV000893685	pathogenic	Renal carnitine transport defect	2024-04-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006795	SCV001162978	pathogenic	Renal carnitine transport defect	2024-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000006795	SCV001194048	pathogenic	Renal carnitine transport defect	2019-12-09	criteria provided, single submitter	clinical testing	NM_003060.3(SLC22A5):c.760C>T(R254*) is classified as pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID 23379544, 17703373 and 20574985. Classification of NM_003060.3(SLC22A5):c.760C>T(R254*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000006795	SCV002020646	pathogenic	Renal carnitine transport defect	2021-09-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000006795	SCV002055813	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
OMIM	RCV000006795	SCV000026991	pathogenic	Renal carnitine transport defect	2007-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000006795	SCV001462808	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000006795	SCV004800866	pathogenic	Renal carnitine transport defect		no assertion criteria provided	clinical testing	PVS1+PM3_VS+PP1+PP4