ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.1340A>G (p.Tyr447Cys)

gnomAD frequency: 0.00001  dbSNP: rs386134218
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000022374 SCV000220879 likely pathogenic Renal carnitine transport defect 2014-11-12 criteria provided, single submitter literature only
GeneDx RCV000478826 SCV000568667 pathogenic not provided 2021-04-29 criteria provided, single submitter clinical testing Transfection of Y447C into CHO cells showed carnitine and tetraethylammonium transport comparable to that in untransfected cells (Amat di San Filippo et al., 2004); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12408185, 22555822, 14665638, 16652335, 21922592, 28841266)
Invitae RCV000022374 SCV000959998 pathogenic Renal carnitine transport defect 2023-11-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 447 of the SLC22A5 protein (p.Tyr447Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 12408185, 28841266). ClinVar contains an entry for this variant (Variation ID: 25418). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC22A5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 16652335). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000022374 SCV002055828 likely pathogenic Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000022374 SCV004037706 pathogenic Renal carnitine transport defect 2023-08-29 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.1340A>G (p.Tyr447Cys) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.1340A>G has been reported in the literature as a biallelic genotype in individuals affected with Systemic Primary Carnitine Deficiency (e.g. Rahbeeni_2002, Dobrowolski_2005, Rose_2012, Frigeni_2017). These data indicate that the variant is likely to be associated with disease. Functional evidence using transfected CHO cells showed that the variant had similar carnitine transport activity as untransfected cells (0%), which may in part be due to mislocalization of the protein: the variant protein did not traffic normally to the cell surface, and was retained within the cytoplasm (Amat di San Filippo_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16652335, 15714519, 28841266, 12408185, 21922592). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000022374 SCV004203574 pathogenic Renal carnitine transport defect 2023-04-20 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000022374 SCV004805089 pathogenic Renal carnitine transport defect 2024-03-17 criteria provided, single submitter research

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