SLC3A1 M467T - GET-Evidence

Curation:
Currentness:

SLC3A1 M467T

(SLC3A1 Met467Thr)


Short summary

Causes cystinuria in a recessive manner, which can lead to kidney stones when symptomatic. This variant is one of the most common cystinuria-causing variants, and may be somewhat milder than other causal variants.

Variant evidence
Computational 2

Other variants within this gene appear to cause the disease as well. Calonge et al. mention that M467 is a highly conserved residue.

See Calonge MJ et al. 1994 (8054986).

Functional 1

Xenopus oocytes injected with variant RNA had nearly abolished amino acid transport activity as compared to control.

See Calonge MJ et al. 1994 (8054986).

Case/Control 4

Significance = 0.00066, OR = 29.

See Calonge MJ et al. 1994 (8054986).

Familial 2

One family documented, LOD = 1.9.

See Calonge MJ et al. 1994 (8054986).

 
Clinical importance
Severity 2

Disease has a moderate effect, causing kidney stones, but is unlikely to be symptomatic.

Treatability 3

In patients with symptoms standard treatment involves adequate hydration and dietary modification and, if these are insufficient, chelation therapy.

Penetrance 5
 

Impact

Moderate clinical importance, pathogenic

(The "moderate clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Cystinuria
5 16 0 63 0.0007

 

Allele frequency

  • C @ chr2:44539792: 0.2% (23/10758) in EVS
  • Frequency shown in summary reports: 0.2% (23/10758)

Publications
 

Calonge MJ, Gasparini P, Chillarón J, Chillón M, Gallucci M, Rousaud F, Zelante L, Testar X, Dallapiccola B, Di Silverio F, et al. Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet. 1994 Apr;6(4):420-5. PubMed PMID: 8054986.

This mutation was homozygous in three siblings with Cystinuria, while the heterozygous parents and fourth sibling were unaffected (LOD = 1.9). Five other patients were heterozygous at this position, two of whom were siblings — presumably these were compound heterozygous. The variant was not seen on any of 126 control chromosomes. It also represents 40% of chromosomes from Cystinuria patients from Spain. Injection of mutated rBAT RNA into Xenopus oocytes had nearly abolished amino acid transport activity compared to wild type. Counting probands, case+: 5, case-: 16, control+: 0, control-: 63. This has significance = 0.00066 and an OR estimated at 29.

Cases/controls case+ case– control+ control– p-value odds ratio
Cystinuria
5 16 0 63 0.0007

 

Dello Strologo L, Pras E, Pontesilli C, Beccia E, Ricci-Barbini V, de Sanctis L, Ponzone A, Gallucci M, Bisceglia L, Zelante L, Jimenez-Vidal M, Font M, Zorzano A, Rousaud F, Nunes V, Gasparini P, Palacín M, Rizzoni G. Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol. 2002 Oct;13(10):2547-53. PubMed PMID: 12239244.

 

Barbosa M, Lopes A, Mota C, Martins E, Oliveira J, Alves S, De Bonis P, Mota Mdo C, Dias C, Rodrigues-Santos P, Fortuna AM, Quelhas D, Lacerda L, Bisceglia L, Cardoso ML. Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients. Clin Genet. 2012 Jan;81(1):47-55. doi: 10.1111/j.1399-0004.2011.01638.x. Epub 2011 Feb 14. PubMed PMID: 21255007.

 

Genomes
 

 

 

Other external references
 

    OMIM
  • Cystinuria
    www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104614
    PolyPhen-2
  • Score: 0.977 (probably damaging)
    Web search results (136 hits -- see all)
  • Balkan Journal of Medical Genetics
    The most frequent mutations were T216M (21.6%) and M467T (14.8%) in the SLC3A1 gene and G105R (22.7%) in the SLC7A9 gene (manuscript in preparation) ...
    www.bjmg.edu.mk/record.asp?subrecordid=1025
  • Kidney International - Cystinuria in children: Distribution ...
    Cystinuria in children: Distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes ... M467T and G105R were the preponderant mutations in SLC3A1 and SLC7A9, ...
    www.nature.com/ki/journal/v62/n4/full/4493208a.html
  • Identification of novel SLC3A1 gene mutations in Spanish ...
    Identification of novel SLC3A1 gene mutations in Spanish cystinuria families and ... A), four point mutations (M467T, R452W, I105R and Y461X), one single base pair deletion ...
    www.ncbi.nlm.nih.gov/pubmed/15691362
  • Cystinuria in children: distribution and frequencies of ...
    Cystinuria in children: distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes. ... M467T and G105R were the preponderant mutations in SLC3A1 and SLC7A9, ...
    www.ncbi.nlm.nih.gov/pubmed/12234283
  • Mutations in the Genomic Deoxyribonucleic Acid for SLC3A1 in ...
    have studied the occurrence of mutations in the SLC3A1 gene, which ... a M467T mutation on their other chromosome, and it was. shown that these mutations were ...
    jcem.endojournals.org/cgi/reprint/83/10/3688.pdf
  • 12 (1), 2009 FIVE NOVEL MUTATIONS IN CYSTINURIA GENES SLC3A1 ...
    and M467T (14.8%) in the SLC3A1 gene and. G105R (22.7%) in the SLC7A9 ... the SLC3A1 gene (one missense and one nonsense) and three in the SLC7A9 gene (two ...
    www.bjmg.edu.mk/UploadedImages/pdf/BJMG_09 vol.12 1.2009.pdf
  • Medline ® Abstract for Reference of 'Cystine stones'
    M467T and G105R were the preponderant mutations in SLC3A1 and SLC7A9, respectively; T216M ... the SLC3A1 gene for type I chromosomes and 25% in the SLC7A9 gene for non-type I ...
    uptodate.com/patients/content/abstract.do?...&refNum=21
  • Cystinuria
    Two of the genes responsible for the disorder, SLC3A1 and SLC7A9, have been identified. ... One of the most common genetic alterations in SLC3A1 is called M467T. ...
    www.cystinuria.com/articles/cystinuria
  • Mutations in the Genomic Deoxyribonucleic Acid for SLC3A1 in ...
    Mutations in the Genomic Deoxyribonucleic Acid for SLC3A1 in Patients with Cystinuria 1 ... was hemizygous for the M467T mutation, it would still indicate ...
    jcem.endojournals.org/cgi/content/full/83/10/3688?ck=nck

Other in silico analyses
 

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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