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

gnomAD frequency: 0.00035  dbSNP: rs142447950

Total submissions: 7

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