Submissions for variant NM_003060.4(SLC22A5):c.761G>A (p.Arg254Gln)

gnomAD frequency: 0.00007  dbSNP: rs200699819

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725646	SCV000338349	uncertain significance	not provided	2015-12-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000725646	SCV000490804	uncertain significance	not provided	2021-08-23	criteria provided, single submitter	clinical testing	Identified with a second SLC22A5 variant in a newborn identified via newborn screening, however, the phase of these variants and clinical follow up were not provided (Gallant et al., 2017); Functional studies demonstrate p.(R254Q) results in 34% carnitine transport activity compared to wildtype (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: 30863740, 28711408, 26828774, 28841266, 34178604)
Invitae	RCV000022342	SCV000632570	likely pathogenic	Renal carnitine transport defect	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 254 of the SLC22A5 protein (p.Arg254Gln). This variant is present in population databases (rs200699819, gnomAD 0.02%). This missense change has been observed in individual(s) with low plasma carnitine levels and primary carnitine deficiency (PMID: 26828774, 28711408; Invitae; http://www.arup.utah.edu/database/OCTN2/OCTN2_display.php). ClinVar contains an entry for this variant (Variation ID: 25389). 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 does not substantially affect 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.
Illumina Laboratory Services, Illumina	RCV000022342	SCV001314431	uncertain significance	Renal carnitine transport defect	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725646	SCV001433791	uncertain significance	not provided	2017-08-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000725646	SCV001715867	likely pathogenic	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000022342	SCV002055757	uncertain significance	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265567	SCV002548263	uncertain significance	not specified	2022-05-06	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.761G>A (p.Arg254Gln) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251486 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (9.9e-05 vs 0.0046), allowing no conclusion about variant significance. c.761G>A has been reported in the literature in compound heterozygous individuals identified through newborn screening (NBS) with biochemical indication of Systemic Primary Carnitine Deficiency but no clinical follow-up provided (Gallant_2017, Yang_2021) or lack of clinical phenotype (Zhou_2019). Furthermore, the variant has been reported in an online database (ARUP, OCTN2 database) as heterozygous occurrence along with other pathogenic variants (such as p.R399W, p.P46S, c.1053-2A>C) in multiple asymptomatic individuals identified through NBS. These reports do not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency. Experimental evidence evaluating an impact on protein function demonstrated the variant retained significant residual carnitine transport activity (Frigeni_2017). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000022342	SCV003816430	likely pathogenic	Renal carnitine transport defect	2022-09-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022342	SCV004201253	pathogenic	Renal carnitine transport defect	2023-10-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000022342	SCV001462809	uncertain significance	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing