Submissions for variant NM_000341.4(SLC3A1):c.1400T>A (p.Met467Lys)

dbSNP: rs121912691

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019744	SCV000751439	pathogenic	Cystinuria	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 467 of the SLC3A1 protein (p.Met467Lys). This variant is present in population databases (rs121912691, gnomAD 0.05%). This missense change has been observed in individual(s) with SLC3A1-related conditions (PMID: 8054986, 19782624, 23532419, 28166740; 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: 18116). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC3A1 protein function. Experimental studies have shown that this missense change affects SLC3A1 function (PMID: 9083097, 18332091). This variant disrupts the p.Met467 amino acid residue in SLC3A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8054986, 8792820, 21677404, 23532419). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000019744	SCV000930177	pathogenic	Cystinuria	2024-12-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415724	SCV004118400	pathogenic	SLC3A1-related disorder	2023-05-16	criteria provided, single submitter	clinical testing	The SLC3A1 c.1400T>A variant is predicted to result in the amino acid substitution p.Met467Lys. This variant was reported in the compound heterozygous and homozygous states in individuals with cystinuria (Calonge et al. 1994. PubMed ID: 8054986; Alghamdi et al. 2020. PubMed ID: 33262960;). In an in vitro model, the p.Met467Lys change was shown to disrupt membrane trafficking of the rBAT protein (Chillarón et al. 1997. PubMed ID: 9083097). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-44539792-T-A). In addition, other missense variants resulting in a different substitution at the same amino acid residue (p.Met467Val, p.Met467Thr, and p.Met467Ile) have also been reported in individuals with cystinuria (Human Gene Mutation Database). Taken together, the c.1400T>A (p.Met467Lys) variant is interpreted as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000019744	SCV005016571	likely pathogenic	Cystinuria	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000019744	SCV000040042	pathogenic	Cystinuria	1994-04-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000019744	SCV001133150	pathogenic	Cystinuria	2019-09-26	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001580112	SCV001809734	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001580112	SCV001956220	pathogenic	not provided		no assertion criteria provided	clinical testing