SLC5A2 N654S - GET-Evidence

Curation:
Currentness:

SLC5A2 N654S

(SLC5A2 Asn654Ser)


Short summary

Some authors report this rare variant as a nonpathogenic polymorphism, others suggest it may cause renal glucosuria in a recessive manner when compound heterozygous with other pathogenic variants.

Variant evidence
Computational

Polyphen 2 ambiguous (“possibly damaging”), BLOSUM100 does not predict Asn to Ser to be disruptive.

Functional -
Case/Control 3
Familial

No significant familial data.

 
Clinical importance
Severity 2

Often asymptomatic

Treatability
Penetrance 5

Hypothesized reports suggest high penetrance, as they treat it as mendelian.

 

Impact

Low clinical importance, Uncertain pathogenic

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

This variant has been seen in controls as well as a handful of published cases of renal glucosuria (which is caused recessively by mutations in this gene). Initial report of this variant dismissed it as a nonpathogenic polymorphism, but other groups have implicated it as pathogenic. Reported findings are sparse, and no single report presents statistically significant findings. The combined data has apparent statistical significance (p = 0.014) but probably suffers from confirmation bias in publication and controls may not be appropriately ethnically matched.

Total cases/controls case+ case– control+ control– p-value odds ratio
Renal Glucosuria
4 76 2 336 0.0138 8.842

 

Allele frequency

  • G @ chr16:31501798: 0.7% (76/10758) in EVS
  • Frequency shown in summary reports: 0.7% (76/10758)

Publications
 

Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003 Nov;14(11):2873-82. PubMed PMID: 14569097.

In a screen of 23 unrelated families, this variant was seen in one case compound heterozygous with 453L (family 21). The authors, however, consider this to be a nonpathogenic variant linked to some unknown causal variant in the family, as the 654S variant was also seen in 1 out of 80 random control chromosomes.

Cases/controls case+ case– control+ control– p-value odds ratio
Renal Glucosuria
1 45 1 79 1.0000 1.756

 

Calado J, Soto K, Clemente C, Correia P, Rueff J. Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. Hum Genet. 2004 Feb;114(3):314-6. Epub 2003 Nov 12. PubMed PMID: 14614622.

A case report of a patient with autosomal recessive renal glucosuria, with non-consanguineous parents. The patient had a frameshift mutation compound heterozygous with this variant. One unaffected sister had the frameshift variant but not this variant. Neither variant was seen in 50 healthy control individuals (100 alleles).

Cases/controls case+ case– control+ control– p-value odds ratio
Renal Glucosuria
- - 0 100 - -

 

Kleta R, Stuart C, Gill FA, Gahl WA. Renal glucosuria due to SGLT2 mutations. Mol Genet Metab. 2004 May;82(1):56-8. PubMed PMID: 15110322.

A case report of a patient compound heterozygous for this variant and T200K. This variant was seen once in a Caucasian in a set of 158 control chromosomes.

Cases/controls case+ case– control+ control– p-value odds ratio
Renal Glucosuria
- - 1 157 - -

 

Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A, Scharf M, Tasic V, Greil J, Brinkert F, Kemper MJ, Santer R. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. 2008 Dec;23(12):3874-9. Epub 2008 Jul 12. PubMed PMID: 18622023.

A screen of 24 individuals from 17 families found this variant heterozygously in three of the 17 families. No controls are reported in this paper.

Cases/controls case+ case– control+ control– p-value odds ratio
Renal Glucosuria
3 31 - - - -

 

Genomes
 

Other external references
 

    dbSNP
  • rs61742739
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.776 (possibly damaging)
    Web search results (11 hits -- see all)
  • 01 Nefrologia 22-1 - Contents + Editorial Board
    ... Glucosuria (FRG) is caused by inactivating mutations in the SLC5A2 ... In this series, the p.N654S allele is report- ed twice; in one case with mild glucosuria, it was the only ...
    www.spnefro.pt/RPNH/PDFs/n1_2008/artigo_09.pdf
  • Twenty-one additional cases of familial renal glucosuria ...
    In all glucosuric individuals tested, at least one SLC5A2 mutation could be identified. ... It is caused by mutations in the SLC5A2 gene, mapped to 16p11.2 and coding for ...
    ndt.oxfordjournals.org/cgi/content/full/23/12/3874
  • SLC5A2 - solute carrier family 5 (sodium/glucose ...
    SLC5A2 coding region of index cases was polymerase chain reaction amplified and sequenced. ... a new missense mutation, T200K, and a known missense mutation, N654S. ...
    www.ihop-net.org/UniPub/iHOP/bng/92202.html
  • Novel compound heterozygous mutations in SLC5A2 are ...
    Familial renal glucosuria is an inherited renal tubular disorder.
    www.medscape.com/medline/abstract/14614622?prt=true
  • PubMed: 14614622
    ... to produce a truncated protein, and the other a p.N654S mutation involving a highly conserved residue. ... that mutations in the SLC5A2 gene are responsible for recessive ...
    www.genome.jp/dbget-bin/www_bget?pubmed+14614622
  • Renal glucosuria due to SGLT2 mutations. - <a href="../public ...
    Renal glucosuria due to SGLT2 mutations. - Robert Kleta, Caroline Stuart, Fred A Gill, William A Gahl ... a new missense mutation, T200K, and a known missense mutation, N654S. ...
    www.curehunter.com/public/pubmed15110322.do
  • Clemente, C (Carla)
    Clemente, C (Carla) :: Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. A novel heterozygous missense ...
    lib.bioinfo.pl/auid:2104201
  • Renal glucosuria due to SGLT2 mutations.
    Isolated renal glucosuria results from mutations in SGLT2, which codes for an active transporter specific for d-glucose and expressed in the luminal membrane of the ...
    www.medscape.com/medline/abstract/15110322
  • Resumos das comunicações orais apresentadas no 20.º Congresso ...
    Os 14 exões de SLC5A2 foram sequenciados directamente a. partir dos produtos de ... das as mutações p.R167fsX186 e p.N654S foram as mais frequente ...
    www.spnefro.pt/RPNH/PDFs/n4_2006/artigo_010.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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