Submissions for variant NM_003060.4(SLC22A5):c.1064C>T (p.Ser355Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Giacomini Lab, University of California, San Francisco	RCV002286640	SCV002576627	uncertain significance	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV002286640	SCV003439233	likely pathogenic	Renal carnitine transport defect	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 355 of the SLC22A5 protein (p.Ser355Leu). 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: 20574985). ClinVar contains an entry for this variant (Variation ID: 1707661). 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. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002286640	SCV005204244	likely pathogenic	Renal carnitine transport defect	2024-06-14	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1064C>T (p.Ser355Leu) results in a non-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 8e-06 in 251464 control chromosomes. c.1064C>T has been reported in the literature in the singly heterozygous and presumed compound heterozygous states in at least 2 individuals affected with clinical or biochemical features of Systemic Primary Carnitine Deficiency (example, Chang_2022, Li_2010). Two publications assessed this variant for transport activity in vitro in CHO and HEK293T cell lines, and found that activity was <5% of wild type controls (example, Frigeni_2017, Koleske_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36568374, 28841266, 36343260, 20574985). ClinVar contains an entry for this variant (Variation ID: 1707661). Based on the evidence outlined above, the variant was classified as likely pathogenic.