ClinVar Miner

Submissions for variant NM_000341.4(SLC3A1):c.1400T>C (p.Met467Thr) (rs121912691)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000019743 SCV000223949 pathogenic Cystinuria 2014-11-12 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000019743 SCV000236503 pathogenic Cystinuria 2013-12-19 criteria provided, single submitter clinical testing
GeneDx RCV000413736 SCV000490814 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The M467T variant in the SLC3A1 gene has been reported in multiple patients with cystinuria (for examples see Calonge et al., 1994; Gucev et al., 2011). Studies have shown that the M467T variant affects the typical function of the protein complex (Chillaron et al., 1997; Bartoccioni et al., 2008). The M467T variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. This change occurs at a residue that is well conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. The M467T variant was observed with a frequency of 0.26%, 23/8,600 alleles, in individuals of European ancestry by the NHLBI Exome Sequencing Project. We interpret M467T as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000019743 SCV000611241 pathogenic Cystinuria 2017-05-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000019743 SCV000731831 pathogenic Cystinuria 2017-09-25 criteria provided, single submitter clinical testing The p.Met467Thr (NM_000341.3 c.1400T>C) variant in SLC3A1 has been reported in a t least 4 homozygous and 11 compound heterozygous individuals with cystinuria ( Halbritter 2015, Tostivint 2017, Gucev 2011, and Calonge 1994), and segregated i n 3 affected siblings in 2 families (Calonge 1994). This variant has also been r eported in ClinVar (Variation ID# 18115) as pathogenic by multiple laboratories. Functional studies provide some support that this variant impacts the protein ( Chillaron 1997, Bartoccioni 2008, and Calonge 1994). This variant has been ident ified in 0.57% (58/10144) of Ashkenazi Jewish chromosomes by the Genome Aggregat ion Database (gnomAD,; dbSNP rs121912691, rs121 912692), though its frequency is low enough to be consistent with a recessive ca rrier frequency. In summary, the p.Met467Thr variant is pathogenic for cystinuri a in an autosomal recessive manner based upon frequent biallelic observations in affected individuals, segregation and functional studies.
Invitae RCV000019743 SCV000751438 pathogenic Cystinuria 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 467 of the SLC3A1 protein (p.Met467Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs121912691, ExAC 0.5%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported as a common SLC3A1 mutation and segregates with cystinuria in several families (PMID: 8054986, 21677404, 8792820). ClinVar contains an entry for this variant (Variation ID: 18115). Experimental studies have shown that this missense change affects protein stability, impairs oligomerization and reduces amino acid transport in vitro (PMID: 18332091, 9083097, 8054986). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000019743 SCV000915917 pathogenic Cystinuria 2018-09-05 criteria provided, single submitter clinical testing The SLC3A1 c.1400T>C (p.Met467Thr) variant is well documented as the most common pathogenic variant associated with type 1 cystinuria. The p.Met467Thr variant has been found in 25 affected homozygotes, 43 affected compound heterozygotes, 22 affected heterozygotes, and 22 unaffected individuals (Calonge et al. 1994; Gasparini et al. 1995; Bisceglia et al. 1996; Harnevik et al. 2001; Botzenhart et al. 2002; Schmidt et al. 2004; Font-Llitjos et al. 2005; Guillen et al. 2005; Skopková et al. 2005; Tanzer et al. 2006; Tanzer et al. 2007; Barbosa et al. 2012; Popovska-Jankovic et al. 2013; Rhodes et al. 2015). The p.Met467Thr variant was found in a heterozygous state in four of 811 controls and is reported at a frequency of 0.00454 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Met467 amino acid residue is very highly conserved in all known SLC3A1 sequences. Calonge et al. (1994) performed functional studies on the p.Met467Thr variant using expression analysis in a Xenopus oocyte system, demonstrating that the variant significantly altered amino acid transport and abolished 80% of normal activity. Chillaron et al. (1997) and Bartoccioni et al. (2008) subsequently demonstrated that the p.Met467Thr variant displays a trafficking defect that maintains an intracellular location rather than being located on the cell surface. Based on the collective evidence, the p.Met467Thr variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000019743 SCV001157133 pathogenic Cystinuria 2019-04-19 criteria provided, single submitter clinical testing The SLC3A1 c.1400T>C; p.Met467Thr variant (rs121912691), is the most common variant in the SLC3A1 gene, and is reported in the literature in the homozygous or compound heterozygous state in multiple individuals and families affected with cystinuria (Bisceglia 1996, Calonge 1994, Gucev 2011, Halbritter 2015, Popovska-Jankovic 2013, Tanzer 2006). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 18115), and is found in the general population with an overall allele frequency of 0.24% (682/282,552 alleles, including 4 homozygotes) in the Genome Aggregation Database. The methionine at codon 467 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, functional analyses of the p.Met467Thr variant protein shows mislocalization leading to decreased transport activity (Bartoccioni 2008, Calonge 1994, Chillaron 1997). Additionally, other variants at this codon (c.1399A>G, p.Met467Val; c.1400T>A, p.Met467Lys) have been reported in individuals with cystinuria and are considered pathogenic (Bisceglia 1996, Calonge 1994, Popovska-Jankovic 2013, Shen 2017). Based on available information, the p.Met467Thr variant is considered to be pathogenic. Pathogenic variants in SLC3A1 are associated with cystinuria (MIM: 220100); both autosomal dominant and autosomal recessive transmission has been reported. References: Bartoccioni P et al. Distinct classes of trafficking rBAT mutants cause the type I cystinuria phenotype. Hum Mol Genet. 2008 Jun 15;17(12):1845-54. Bisceglia L et al. Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism. Hum Genet. 1996 Oct;98(4):447-51. Calonge MJ et al. Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet. 1994 Apr;6(4):420-5. Chillaron J et al. An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. J Biol Chem. 1997 Apr 4;272(14):9543-9. Gucev Z et al. Cystinuria AA (B): digenic inheritance with three mutations in two cystinuria genes. J Genet. 2011 Apr;90(1):157-9. Halbritter J et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol. 2015 Mar;26(3):543-51. Popovska-Jankovic K et al. Molecular characterization of cystinuria in south-eastern European countries. Urolithiasis. 2013 Feb;41(1):21-30. Shen L et al. Clinical and genetic characterization of Chinese pediatric cystine stone patients. J Pediatr Urol. 2017 Dec;13(6):629.e1-629.e5. Tanzer F et al. Analysis of a 1-year-old cystinuric patient with recurrent renal stones. Int J Urol. 2006 Oct;13(10):1347-9.
Molecular Biology Laboratory, Fundació Puigvert RCV000019743 SCV001425259 likely pathogenic Cystinuria 2020-02-01 criteria provided, single submitter research
OMIM RCV000019743 SCV000040041 pathogenic Cystinuria 2005-01-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000019743 SCV001142318 pathogenic Cystinuria 2020-01-06 no assertion criteria provided curation NM_000341.3:c.1400T>C in the SLC3A1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Tostivint I et al. identified this variant in at least 12 patients with cystinuria, including 2 homozygotes and 10 compound heterozygotes: c.266T>C/c.1400T>C; c.1400T>C/c.592delG; c.1400T>C/c.1354C>T; c.1400T>C/c.1500+1G>T; etc.(PMID: 28646536 ). The p.Met467Thr (NM_000341.3 c.1400T>C) variant in SLC3A1 has also been found segregating in 3 affected siblings in one family (PMID: 8054986). Functional studies have shown that this missense change affects protein stability, impairs oligomerization and reduces amino acid transport in vitro (PMID: 18332091; 9083097; 8054986). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP1, PP4.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000413736 SCV001550787 pathogenic not provided no assertion criteria provided clinical testing The SLC3A1 p.Met467Thr variant was identified in 19 of 782 proband chromosomes (frequency: 0.0448) from individuals or families with Cystinuria and kidney stones (Rhodes_2015_PMID:25964309; Halbritter_2015_PMID:25296721; Popovska-Jankovic_2013_PMID:23532419). The variant was identified in dbSNP (ID: rs121912691) and in ClinVar (classified as pathogenic by 7 submitters including GeneDx and Invitae; associated condition is Cystinuria). The variant was identified in control databases in 682 of 282552 chromosomes (4 homozygous) at a frequency of 0.002414 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 58 of 10362 chromosomes (freq: 0.005597), European (non-Finnish) in 517 of 128916 chromosomes (freq: 0.00401), Other in 19 of 7206 chromosomes (freq: 0.002637), Latino in 35 of 35416 chromosomes (freq: 0.000988), European (Finnish) in 24 of 25124 chromosomes (freq: 0.000955), African in 20 of 24972 chromosomes (freq: 0.000801) and South Asian in 9 of 30610 chromosomes (freq: 0.000294); it was not observed in the East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Met467 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. However, functional studies using Xenopus oocytes showed M467T mutants to have reduced transport activity (Bartoccioni_2008_PMID:18332091, Chillarón_1997_PMID:9083097, Calonge_1994_PMID:8054986). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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