ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.51C>G (p.Phe17Leu)

gnomAD frequency: 0.00005  dbSNP: rs11568520
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000489029 SCV000111951 pathogenic not provided 2014-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000489029 SCV000577177 pathogenic not provided 2022-01-04 criteria provided, single submitter clinical testing Functional analysis of p.(F17L) found that it is associated with decreased function, impaired carnitine transport, and distinct subcellular localization (Urban et al., 2006); 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: 25132046, 20074989, 28711408, 23520115, 20574985, 28186590, 19940846, 26828774, 28841266, 29132460, 30904546, 31364285, 31472821, 31980526, 33050909, 33757571, 33560599, 32778825, 33181153, 16931768)
Invitae RCV000022297 SCV000632555 pathogenic Renal carnitine transport defect 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 17 of the SLC22A5 protein (p.Phe17Leu). This variant is present in population databases (rs11568520, gnomAD 0.2%). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 20074989, 20574985, 23520115). ClinVar contains an entry for this variant (Variation ID: 25350). 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: 16931768). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000489029 SCV000886118 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing The SLC22A5 c.51C>G; p.Phe17Leu variant (rs11568520) has been described as a common pathogenic variant in the Chinese population (Chen 2013) and has been identified in the homozygous and compound heterozygous states in patients affected with and newborns screening positive for primary carnitine deficiency (Chen 2013, Han 2014, Lee 2010, Li 2010). It is reported as pathogenic in ClinVar (Variation ID: 25350) and is observed in the general population at a low overall frequency of 0.01% (29/275524 alleles) in the Genome Aggregation Database. The phenylalanine at codon 17 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant to be deleterious to protein function. Additionally, functional analysis of the variant protein demonstrates defective trafficking to the plasma membrane and reduced enzymatic function (Urban 2006). Based on available information, this variant is considered pathogenic. References: Chen Y et al. Carnitine uptake defect (primary carnitine deficiency): risk in genotype-phenotype correlation. Hum Mutat. 2013;34(4):655. Han L et al. Analysis of genetic mutations in Chinese patients with systemic primary carnitine deficiency. Eur J Med Genet. 2014 Oct;57(10):571-5. Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010;31(8):E1632-51. Urban T et al. Functional genetic diversity in the high-affinity carnitine transporter OCTN2 (SLC22A5). Mol Pharmacol. 2006;70(5):1602-11.
Myriad Genetics, Inc. RCV000022297 SCV001193897 pathogenic Renal carnitine transport defect 2020-01-02 criteria provided, single submitter clinical testing NM_003060.3(SLC22A5):c.51C>G(F17L) is classified as pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID 18337137, 30904546, 30838026, 29132460, 28841266, 25132046, 23520115, 23798014, 20574985 and 16931768. Classification of NM_003060.3(SLC22A5):c.51C>G(F17L) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity Omics RCV000022297 SCV002020645 pathogenic Renal carnitine transport defect 2022-11-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000022297 SCV002055785 pathogenic Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Giacomini Lab, University of California, San Francisco RCV000022297 SCV002576641 pathogenic Renal carnitine transport defect 2022-10-03 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000022297 SCV003922884 pathogenic Renal carnitine transport defect 2023-03-16 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.51C>G (p.Phe17Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249224 control chromosomes (gnomAD), predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.0016 vs 0.0046), allowing no conclusion about variant significance. c.51C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Lin_2021, Liammongkolkul_2023). These data indicate that the variant is very likely to be associated with disease. The variant was found to result in decreased L-carntine transport, with the most pronounced variant effect resulting in <20% normal activity which may be the result of incorrect localization to the cytoplasm instead of the plasma membrane (e.g. Urban_2006, Frigeni_2017). Eight ClinVar submitters have assessed the variant since 2014: all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000022297 SCV004201248 pathogenic Renal carnitine transport defect 2023-10-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV000022297 SCV001458679 pathogenic Renal carnitine transport defect 2020-09-16 no assertion criteria provided clinical testing

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