ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.1196G>A (p.Arg399Gln)

gnomAD frequency: 0.00002  dbSNP: rs121908891
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000006793 SCV001228413 pathogenic Renal carnitine transport defect 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 399 of the SLC22A5 protein (p.Arg399Gln). This variant is present in population databases (rs121908891, gnomAD 0.007%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 11715001, 28841266). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6424). 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: 11715001). This variant disrupts the p.Arg399 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20027113, 20574985, 25132046, 28841266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000006793 SCV001360662 pathogenic Renal carnitine transport defect 2019-07-05 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.1196G>A (p.Arg399Gln) results in a 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 allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). c.1196G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Wang_2001). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein resulted in markedly reduced carnitine transport compared to the wild-type OCTN2 (5%; Frigeni_2017, Wang_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV001532526 SCV001748128 pathogenic not provided 2021-09-01 criteria provided, single submitter clinical testing
GeneDx RCV001532526 SCV001789318 pathogenic not provided 2020-12-09 criteria provided, single submitter clinical testing Expression of R399Q in CHO cells reduced carnitine transport to 5% of normal transport activity (Wang et al., 2001); Not observed at a significant frequency 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: 28841266, 28711408, 11715001, 16652335, 27931018, 15714519, 28186590)
Genome-Nilou Lab RCV000006793 SCV001821565 pathogenic Renal carnitine transport defect 2021-07-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV000006793 SCV004201299 pathogenic Renal carnitine transport defect 2023-07-28 criteria provided, single submitter clinical testing
OMIM RCV000006793 SCV000026989 pathogenic Renal carnitine transport defect 2001-11-01 no assertion criteria provided literature only
Natera, Inc. RCV002226444 SCV002078346 pathogenic Decreased circulating carnitine concentration 2021-04-05 no assertion criteria provided clinical testing
Natera, Inc. RCV000006793 SCV002107468 pathogenic Renal carnitine transport defect 2021-04-05 no assertion criteria provided clinical testing

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