Submissions for variant NM_003060.4(SLC22A5):c.844C>T (p.Arg282Ter)

gnomAD frequency: 0.00005  dbSNP: rs121908886

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000006785	SCV000452735	pathogenic	Renal carnitine transport defect	2017-04-28	criteria provided, single submitter	clinical testing	The SLC22A5 c.844C>T (p.Arg282Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg282Ter variant has been reported in at least seven studies in a total of ten individuals with systemic primary carnitine deficiency, including in three in a homozygous state, in three in a compound heterozygous state, and in four in a heterozygous state (Burwinkel et al. 1999; Wang et al. 1999; Vaz et al. 1999; Dobrowolski et al. 2005; Li et al. 2010; Kilic et al. 2012; Rose et al. 2012). The mother of one of the heterozygous patients was also a carrier of the variant but was asymptomatic. Control data are not available for the p.Arg282Ter variant, which is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. The p.Arg282Ter variant has also been associated with an unconventional splicing defect (Burwinkel et al. 1999). Fibroblasts from one of the homozygous individuals were shown to exhibit absent saturable carnitine transport and 25% of the normal mRNA expression. Functional studies in Chinese hamster ovary cells showed that transfection with the wildtype protein could increase carnitine transport but that expression of the p.Arg282Ter variant protein could not (Wang et al. 1999). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg282Ter variant is classified as pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006785	SCV000632573	pathogenic	Renal carnitine transport defect	2024-11-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg282*) 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 (rs121908886, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with primary carnitine deficiency (PMID: 10051646, 10425211, 10480371, 21922592). ClinVar contains an entry for this variant (Variation ID: 6416). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000579046	SCV000680583	pathogenic	not provided	2020-07-30	criteria provided, single submitter	clinical testing	Reported in patients with an abnormal newborn screen for primary carnitine deficiency who did not have a second variant described (Li et al., 2010); 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; This variant is associated with the following publications: (PMID: 23090741, 10051646, 25087612, 25525159, 15714519, 20574985, 12204000, 10480371, 29636919, 28841266, 23430869, 21922592, 10425211)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006785	SCV000920216	pathogenic	Renal carnitine transport defect	2018-09-27	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.844C>T (p.Arg282X) 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. The variant allele was found at a frequency of 4.9e-05 in 121404 control chromosomes (gnomAD). c.844C>T has been reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Wang 1999, Burwinkel 1999, Dobrowolski 2005, Rose 2012). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Wang 1999, Frigeni 2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000579046	SCV001247712	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000006785	SCV001474454	pathogenic	Renal carnitine transport defect	2020-05-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000006785	SCV002055816	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000006785	SCV002811092	pathogenic	Renal carnitine transport defect	2024-06-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006785	SCV004201289	pathogenic	Renal carnitine transport defect	2024-03-19	criteria provided, single submitter	clinical testing
OMIM	RCV000006785	SCV000026981	pathogenic	Renal carnitine transport defect	1999-08-02	no assertion criteria provided	literature only
Natera, Inc.	RCV000006785	SCV001462813	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754250	SCV005345673	pathogenic	SLC22A5-related disorder	2024-03-18	no assertion criteria provided	clinical testing	The SLC22A5 c.844C>T variant is predicted to result in premature protein termination (p.Arg282*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with systemic primary carnitine deficiency (see, for example, Wang et al. 1999. PubMed ID: 10051646; Vaz et al. 1999. PubMed ID: 10480371; Frigeni et al. 2017. PubMed ID: 28841266; Lamhonwah et al. 2018. PubMed ID: 29636919; Lin et al. 2021. PubMed ID: 34863234). In vitro functional studies demonstrate that this variant results in a loss of protein expression and carnitine transport activity (Wang et al. 1999. PubMed ID: 10051646; Vaz et al. 1999. PubMed ID: 10480371). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. Nonsense variants in SLC22A5 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.