Submissions for variant NM_003060.4(SLC22A5):c.272A>G (p.Asn91Ser)

gnomAD frequency: 0.00039  dbSNP: rs546442503

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530205	SCV000632543	pathogenic	Renal carnitine transport defect	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 91 of the SLC22A5 protein (p.Asn91Ser). This variant is present in population databases (rs546442503, gnomAD 0.03%). This missense change has been observed in individual(s) with 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: 460405). 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.
Illumina Laboratory Services, Illumina	RCV000530205	SCV001313088	uncertain significance	Renal carnitine transport defect	2018-01-12	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	RCV001556640	SCV001778255	uncertain significance	not provided	2021-12-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000530205	SCV002055843	uncertain significance	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000530205	SCV002576692	uncertain significance	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701619	SCV005204915	uncertain significance	not specified	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.272A>G (p.Asn91Ser) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 179466 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.272A>G has been reported in the literature in at least one individual affected with a reported renal carnitine transport defect without reported genotype or second variant (e.g. Pochini_2019). This report does not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30523710). ClinVar contains an entry for this variant (Variation ID: 460405). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001556640	SCV005411859	uncertain significance	not provided	2024-08-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV002226470	SCV002078290	uncertain significance	Decreased circulating carnitine concentration	2020-10-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000530205	SCV002107413	uncertain significance	Renal carnitine transport defect	2020-10-16	no assertion criteria provided	clinical testing