2-44312653-T-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM5PP5_Very_StrongBP4
The NM_000341.4(SLC3A1):c.1400T>C(p.Met467Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00316 in 1,613,910 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M467K) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 11 hom. )
Consequence
SLC3A1
NM_000341.4 missense
NM_000341.4 missense
Scores
6
7
6
Clinical Significance
Conservation
PhyloP100: 6.98
Genes affected
SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-44312653-T-A is described in Lovd as [Pathogenic].
PP5
Variant 2-44312653-T-C is Pathogenic according to our data. Variant chr2-44312653-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44312653-T-C is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.09155038). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC3A1 | NM_000341.4 | c.1400T>C | p.Met467Thr | missense_variant | 8/10 | ENST00000260649.11 | NP_000332.2 | |
| SLC3A1 | XM_011533047.4 | c.1400T>C | p.Met467Thr | missense_variant | 8/10 | XP_011531349.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC3A1 | ENST00000260649.11 | c.1400T>C | p.Met467Thr | missense_variant | 8/10 | 1 | NM_000341.4 | ENSP00000260649.6 | ||
| ENSG00000285542 | ENST00000649044.1 | n.*1411T>C | non_coding_transcript_exon_variant | 13/15 | ENSP00000497083.1 | |||||
| ENSG00000285542 | ENST00000649044.1 | n.*1411T>C | 3_prime_UTR_variant | 13/15 | ENSP00000497083.1 |
Frequencies
GnomAD3 genomes 0.00235 AC: 358AN: 152198Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00250 AC: 627AN: 251156Hom.: 4 AF XY: 0.00266 AC XY: 361AN XY: 135726
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:26
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cystinuria Pathogenic:18
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Likely pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Nov 12, 2014 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 09, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 467 of the SLC3A1 protein (p.Met467Thr). This variant is present in population databases (rs121912691, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cystinuria (PMID: 8054986, 8792820, 21677404). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18115). 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: 8054986, 9083097, 18332091). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Jul 05, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 24, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 05, 2018 | 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; SkopkovÅ 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2024 | Variant summary: SLC3A1 c.1400T>C (p.Met467Thr) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 251156 control chromosomes in the gnomAD database, including 4 homozygotes. c.1400T>C has been reported in the literature in multiple individuals affected with Cystinuria in homozygous (examples: Calonge_1994, Tanzer_2007, Harnevik_2001), compound heterozygous (Harnevik_2001) and heterozygous state (examples: Tanzer_2007, Harnevik_2001). The variant also segregated with the disease (Calonge_1994). These data indicate that the variant is very likely to be associated with disease. Multiple studies have shown that this variant impairs normal transport activity of the protein (examples: Calonge_1994, Bartoccioni_2008). A different variant affecting this residue (c.1400T>A, p.Met467Lys) has been classified pathogenic in ClinVar (CV ID 18116). The following publications have been ascertained in the context of this evaluation (PMID: 18332091, 8054986, 17880288, 11748844). ClinVar contains an entry for this variant (Variation ID: 18115). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Dec 19, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 25, 2017 | 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, http://gnomad.broadinstitute.org; 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Oct 08, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 10, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cystinuria (MIM#220100). (I) 0108 - This gene is associated with both recessive and dominant disease. Although predominantly associated with recessive disease, there are reports of affected carriers (PMID: 15635077, 25964309). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to threonine. (I) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (674 heterozygotes, 4 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (21 heterozygotes, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Alpha amylase catalytic domain or motif (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as a common pathogenic variant in patients with cystinuria (ClinVar, PMID: 8054986, 25964309). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2019 | Reported as the most common pathogenic variant in SLC3A1, accounting for 29.3% of disease-causing alleles across multiple ethnic groups (Eggermann et al., 2012); Published functional studies demonstrate the absence of transport activity in mammalian cells transfected with the M467T variant (Bartoccioni et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 14991253, 12234283, 10798361, 8054986, 18332091, 25296721, 9083097, 21677404, 8792820, 12820697, 10805464, 17010017, 30609409, 28812535, 15635077, 22480232, 16138908, 11748844, 28646536, 31589614, 10562926, 30069816, 33226606) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 21, 2024 | PP1, PP3, PM3_very_strong, PS3_supporting, PS4_moderate - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 13, 2024 | The c.1400T>C (p.M467T) alteration is located in exon 8 (coding exon 8) of the SLC3A1 gene. This alteration results from a T to C substitution at nucleotide position 1400, causing the methionine (M) at amino acid position 467 to be replaced by a threonine (T). Based on data from gnomAD, the C allele has an overall frequency of 0.241% (682/282552) total alleles studied. The highest observed frequency was 0.56% (58/10362) of Ashkenazi Jewish alleles. This is the most common alteration seen in individuals with cystinuria, accounting for approximately 30% of the known disease-causing alleles and detectable in nearly all ethnic groups (Eggermann, 2012). Numerous individuals affected with cystinuria and harboring this variant, in either the homozygous or compound heterozygous state, have been reported in the literature, and this alteration has been found to segregate with disease in multiple families (Calonge, 1994; Harnevik, 2001; Font-Llitjos, 2005; Halbritter, 2015; Rhodes, 2015). This amino acid position is well conserved in available vertebrate species. Functional studies of this variant, as well as a different variant at the same amino acid (p.M467K), have demonstrated that these alterations lead to delayed transport of the protein and failure to form functional heterotetramers (Calonge, 1994; Chillaron, 1997; Bartoccioni, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jun 24, 2021 | ACMG classification criteria: PS3, PM3, PP3 - |
SLC3A1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 22, 2024 | The SLC3A1 c.1400T>C variant is predicted to result in the amino acid substitution p.Met467Thr. This variant has been reported to be causative for cystinuria in the homozygous and compound heterozygous state in multiple unrelated individuals (Calonge et al. 1994. PubMed: 8054986; Halbritter et al. 2015. PubMed: 25296721). Functional studies demonstrate the p.Met467Thr variant results in destabilized heterodimers (Bartoccioni et al. 2008. PubMed: 18332091). Autosomal recessive and dominant inheritance of pathogenic variants in the SLC3A1 gene has been reported previously (OMIM #220100); however, heterozygous carriers of the p.Met467Arg variant have been reported as unaffected (Calonge et al. 1994. PubMed: 8054986; Gucev et al. 2011. PubMed: 21677404). This variant is reported in 0.56% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic for autosomal recessive SLC3A1-related disorders. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;D;D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;N;.;N;N;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
.;T;T;T;T;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
0.39, 0.77
.;B;P;.;.;.;.;.
Vest4
MVP
MPC
0.023
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at