Submissions for variant NM_003060.4(SLC22A5):c.377C>A (p.Ser126Tyr)

gnomAD frequency: 0.00003  dbSNP: rs568906114

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822785	SCV000963602	uncertain significance	Renal carnitine transport defect	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 126 of the SLC22A5 protein (p.Ser126Tyr). This variant is present in population databases (rs568906114, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SLC22A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 664649). 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%. 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.
Illumina Laboratory Services, Illumina	RCV000822785	SCV001313092	uncertain significance	Renal carnitine transport defect	2018-02-09	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001547861	SCV001767661	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000822785	SCV002055848	uncertain significance	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000822785	SCV002785920	uncertain significance	Renal carnitine transport defect	2024-05-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV002226498	SCV002078302	uncertain significance	Decreased circulating carnitine concentration	2020-08-06	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000822785	SCV002107425	uncertain significance	Renal carnitine transport defect	2020-08-06	no assertion criteria provided	clinical testing