Submissions for variant NM_003060.4(SLC22A5):c.1556_1559dup (p.Ile521fs)

dbSNP: rs386134225

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000022387	SCV000220540	likely pathogenic	Renal carnitine transport defect	2014-07-23	criteria provided, single submitter	literature only
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000022387	SCV000890886	pathogenic	Renal carnitine transport defect	2016-07-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022387	SCV001482243	pathogenic	Renal carnitine transport defect	2021-02-13	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1556_1559dupACAC (p.Ile521HisfsX3) 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 was absent in 251418 control chromosomes. c.1556_1559dupACAC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency and has been subsequently cited by others (example, Schimmenti_2007, Rose_2012, Longo_2016, Frigeni_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing one overlapping publication utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000022387	SCV002055836	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004730854	SCV005336386	pathogenic	SLC22A5-related disorder	2024-05-17	no assertion criteria provided	clinical testing	The SLC22A5 c.1556_1559dupACAC variant is predicted to result in a frameshift and premature protein termination (p.Ile521Hisfs*3). This variant has been reported in the presumed compound heterozygous state (along with the established pathogenic variant p.Pro46Ser) in at least two individuals with primary carnitine deficiency (Schimmenti et al. 2007. PubMed ID: 17126586; Frigeni et al. 2017. PubMed ID: 28841266). Cultured fibroblasts from both individuals have an almost complete loss of carnitine transport activity (3.4 - 4.2%) compared to fibroblasts from healthy controls (Schimmenti et al. 2007. PubMed ID: 17126586; Frigeni et al. 2017. PubMed ID: 28841266). This variant has not been reported in the gnomAD database, indicating this variant is rare. Frameshift variants in SLC22A5 are expected to be pathogenic. This variant is interpreted as pathogenic.