ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.865C>T (p.Arg289Ter)

gnomAD frequency: 0.00002  dbSNP: rs386134212
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000022357 SCV000632575 pathogenic Renal carnitine transport defect 2024-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg289*) 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 (rs386134212, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with primary carnitine deficiency (PMID: 15714519, 25132046). ClinVar contains an entry for this variant (Variation ID: 25404). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000022357 SCV001360661 pathogenic Renal carnitine transport defect 2021-06-25 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.865C>T (p.Arg289X) 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 in the HGMD database. The variant allele was found at a frequency of 1.6e-05 in 251492 control chromosomes. c.865C>T has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with Systemic Primary Carnitine Deficiency (example, Dobrowlski_2005, Kilic_2011, Han_2014, Frigeni_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal carnitine transport activity in patient derived fibroblasts (example, 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 (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000022357 SCV002055817 pathogenic Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000022357 SCV002802082 pathogenic Renal carnitine transport defect 2024-02-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV000022357 SCV004201293 pathogenic Renal carnitine transport defect 2024-02-16 criteria provided, single submitter clinical testing
Counsyl RCV000022357 SCV001132289 likely pathogenic Renal carnitine transport defect 2015-04-22 no assertion criteria provided clinical testing
Natera, Inc. RCV000022357 SCV001462815 pathogenic Renal carnitine transport defect 2020-09-16 no assertion criteria provided clinical testing

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