ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.428C>T (p.Pro143Leu)

gnomAD frequency: 0.00001  dbSNP: rs1178584184
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508023 SCV000605137 likely pathogenic not specified 2017-04-13 criteria provided, single submitter clinical testing
Counsyl RCV000673165 SCV000798339 likely pathogenic Renal carnitine transport defect 2018-03-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000673165 SCV000953893 pathogenic Renal carnitine transport defect 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 143 of the SLC22A5 protein (p.Pro143Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20074989, 28753539, 30863740). 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: 440273). 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: 28841266). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000673165 SCV002055803 likely pathogenic Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Giacomini Lab, University of California, San Francisco RCV000673165 SCV002576696 uncertain significance Renal carnitine transport defect 2022-10-03 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000673165 SCV002766212 pathogenic Renal carnitine transport defect 2022-11-04 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.428C>T (p.Pro143Leu) 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 8e-06 in 251496 control chromosomes (gnomAD). c.428C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Primary Carnitine Deficiency, identified through newborn screening (e.g. Lee_2010, Sun_2017, Li_2022). Experimental evidence evaluating an impact on protein function demonstrated the variant significantly impairs carnitine transport activity (<10% of wild-type) (Frigeni_2017). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and four classified it as likely pathogenic, one as pathogenic, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000673165 SCV002815104 likely pathogenic Renal carnitine transport defect 2021-09-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV000673165 SCV004201286 likely pathogenic Renal carnitine transport defect 2024-03-26 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000673165 SCV005418400 likely pathogenic Renal carnitine transport defect criteria provided, single submitter clinical testing PM2_Supporting+PM3_Strong+PP4+PS3_Supporting
Natera, Inc. RCV000673165 SCV001462801 likely pathogenic Renal carnitine transport defect 2020-09-16 no assertion criteria provided clinical testing

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