ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.529A>G (p.Met177Val)

gnomAD frequency: 0.00028  dbSNP: rs145068530
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434160 SCV000515915 likely pathogenic not provided 2023-09-07 criteria provided, single submitter clinical testing Functional analysis found p.(M177V) is associated with significantly impaired carnitine transport compared to wild-type (Frigeni et al., 2017); 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: 26828774, 20574985, 28841266, 36343260)
Labcorp Genetics (formerly Invitae), Labcorp RCV000694962 SCV000823434 uncertain significance Renal carnitine transport defect 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 177 of the SLC22A5 protein (p.Met177Val). This variant is present in population databases (rs145068530, gnomAD 0.1%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20574985). ClinVar contains an entry for this variant (Variation ID: 379230). 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, 36343260). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab RCV000694962 SCV002055751 likely pathogenic Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Giacomini Lab, University of California, San Francisco RCV000694962 SCV002576660 likely pathogenic Renal carnitine transport defect 2022-10-03 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002469147 SCV002766213 uncertain significance not specified 2022-11-17 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.529A>G (p.Met177Val) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 282892 control chromosomes (gnomAD), predominantly at a frequency of 0.00088 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00088 vs 0.0046), allowing no conclusion about variant significance. c.529A>G has been reported in the literature in at least one compound heterozygous individuals affected with Systemic Primary Carnitine Deficiency (Li_2010). These data do not allow any conclusion about variant significance. Functional evidence obtained using stably transfected CHO cells demonstrated the variant had ~14% of normal activity (Frigeni_2017). Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and three as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV000694962 SCV004201250 likely pathogenic Renal carnitine transport defect 2024-03-21 criteria provided, single submitter clinical testing
Counsyl RCV000694962 SCV001132486 uncertain significance Renal carnitine transport defect 2018-11-19 no assertion criteria provided clinical testing

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