ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.605T>C (p.Leu202Pro)

gnomAD frequency: 0.00035  dbSNP: rs142447950
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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 RCV000554108 SCV000632559 pathogenic Renal carnitine transport defect 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 202 of the SLC22A5 protein (p.Leu202Pro). This variant is present in population databases (rs142447950, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of primary carnitine deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 460410). 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%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000554108 SCV000895658 uncertain significance Renal carnitine transport defect 2018-10-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000554108 SCV002055849 uncertain significance Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Giacomini Lab, University of California, San Francisco RCV000554108 SCV002576713 uncertain significance Renal carnitine transport defect 2022-10-03 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV003480672 SCV004227123 uncertain significance not provided 2023-02-23 criteria provided, single submitter clinical testing PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782429 SCV005395156 uncertain significance not specified 2024-09-09 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.605T>C (p.Leu202Pro) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of 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 0.00014 in 251492 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00014 vs 0.0046), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.605T>C in individuals affected with Systemic Primary Carnitine Deficiency has been reported in the literature. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in vitro (example, Koleske_2022). The following publication has been ascertained in the context of this evaluation (PMID: 36343260). ClinVar contains an entry for this variant (Variation ID: 460410). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000554108 SCV001458332 uncertain significance Renal carnitine transport defect 2020-05-01 no assertion criteria provided clinical testing

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