SDHB S163P - GET-Evidence

Curation:
Currentness:

SDHB S163P

(SDHB Ser163Pro)


Short summary

We evaluate as uncertain but presumed benign. One report linked this variant to Cowden-like syndromes, but the significance of their findings is unclear and other reports treat this as a non-pathological variation.

Variant evidence
Computational 1

Polyphen 2 predicts benign effect

Functional -
Case/Control 2

Same allele frequency in cases and controls

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Uncertain benign

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

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • G @ chr1:17354297: 1.0% (112/10758) in EVS
  • G @ chr1:17226883: 1.6% (2/128) in GET-Evidence
  • Frequency shown in summary reports: 1.0% (112/10758)

Publications
 

Castellano M, Mori L, Giacchè M, Agliozzo E, Tosini R, Panarotto A, Cappelli C, Mulatero P, Cumetti D, Veglio F, Agabiti-Rosei E. Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients. Ann N Y Acad Sci. 2006 Aug;1073:156-65. PubMed PMID: 17102082.

Considered a nonpathogenic polymorphism.

Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008 Aug;83(2):261-8. PubMed PMID: 18678321; PubMed Central PMCID: PMC2495063.

This study implicates this variant as being much more common in a group of patients with Cowden or Cowden-like syndrome (which are inherited in a dominant manner, generally attributed to mutations in the gene PTEN) that lacked PTEN mutations and had elevated MnSOD protein levels. In a screen for SDHB mutations in these 74 patients, they found this variant heterozygously in two patients, and report not seeing it in 700 control chromosomes (equivalent to 350 individuals) (white of Northern/Western European ancestry).

They report a p-value of p<0.001 for the combined presence of this variant (H50R) and two other variants (G12S and S163P) in their cases (total of 8) compared to controls. This however is combining data for multiple variants. Counting alleles for this variant in particular, their data reports: case+ = 2, case- = 146, control+ = 0, control- = 700. A two-tailed Fisher’s Exact test gives p=0.03.

However, this study’s reported control data are suspicious and highly divergent from other reports — the authers state “all 700 controls had the entire sequence of SDHB, SDHC, and SDHD sequenced and no variants identified”. Both exome variation server data and low coverage CEU data report SDHB, SDHC, and SDHD variants with allele frequencies that diverge from the claim made regarding the 700 controls with extremely high significance (and, conversely, show no significant difference from the cases reported here). It seems very likely that some error was made in the analysis of the controls in this paper; without this statistical data the hypothesis that these genes are involved in Cowden or Cowden-like syndromes is seriously weakened.

At the time it was published, the authors were aware of already existing reports for the three most common variants of allele frequencies ranging from 1-3%. They forward two explanations for their controls being different, both of which are quite weak. (1) The ethnic groups samples (Spanish, French Canadian) may be significantly different from that studied in their paper (whites of Western/Northern European ancestry). This is implausible because later allele frequency data from the CEU cohort (which perfectly matches their description: Western/Northern European ancestry) confirms the 1-3% allele frequencies and is significantly divergent from reported 700 controls. (2) The 700 controls excluded individuals with symptoms of the disease, while other frequency data was from unselected populations. This is implausible because it posits a high penetrance dominant phenotype effect (obvious enough to cause exclusion of carriers) — this is a surprising hypothesis for such a common variant. If this were true, we would expect such an effect to be reported by now; indeed, we would expect significantly more of these carriers to be represented in the cases in this paper — this is not the case, frequencies in cases reported in the paper are not significantly different from the allele frequencies of the population at large.

The paper reports some functional findings, but in vitro findings do not necessarily predict a phenotype and should be interpreted with caution. (1) These variants are common enough that case/control or familial findings should be readily found and reproduced, and with data consistent with general population allele frequency data reported elsewhere. (2) In cases of extremely rare variants functional data may be relied upon to establish a particular variant’s effect, but in such cases other variants for the same gene (with similar functional data) should have a pathogenic effect supported with strong statistical evidence.

Genomes
 

 

GS19669 - var-GS19669-1100-36-ASM
het G @ chr1:17226884

 

Other external references
 

    dbSNP
  • rs33927012
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the SDHB gene
    Hereditary Paraganglioma-Pheochromocytoma Syndromes
    Sarcosinemia
    SDHB-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SDHB
    PolyPhen-2
  • Score: 0 (benign)
    Web search results (19 hits -- see all)
  • Candidate gene mutation analysis in bilateral adrenal ...
    mutations in RET, VHL, SDHB, and SDHD in comparatively large series of bilateral ... (SDHB A6A and S163P; SDHD H50R and S68S), because they have also been ...
    erc.endocrinology-journals.org/cgi/reprint/14/2/453.pdf
  • Genetic mutation screening in an italian cohort of ...
    Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma ... detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD ...
    www.ncbi.nlm.nih.gov/pubmed/17102082
  • No mutations but an increased frequency of SDHx polymorphisms ...
    ... of amino-acid coding polymorphisms (S163P in SDHB as well as G12S and H50R ... leading to an amino acid change (S163P in SDHB as well as G12S and H50R in ...
    erc.endocrinology-journals.org/cgi/content/full/12/4/1011
  • SDHD - succinate dehydrogenase complex, subunit D, integral ...
    SDHB and SDHD mutations are widely distributed along the genes with no apparent hot spots. ... detected missense ( SDHB S163P, SDHD H50R and G12S), synonymous ( SDHB A6A, SDHD ...
    www.ihop-net.org/UniPub/iHOP/gs/92078.html
  • Type I- 95%
    Gene name SWISS-PROT ID Variant site Phosphorylation site SWISS-PROT variant ID ... CK2 (0.813) neuroblastoma 8047138 CAV3 P56539 S61R 61 VAR_026696 PKC ...
    www.nih.go.kr/phosphovariant/html/family_whole/TypeI-_95.txt
  • Genetic mutation screening in an italian cohort of ...
    Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma ... detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD ...
    www.medscape.com/medline/abstract/17102082
  • SDHB - succinate dehydrogenase complex, subunit B, iron ...
    SDHB and SDHD mutations are widely distributed along the genes with no apparent hot spots. ... detected missense ( SDHB S163P, SDHD H50R and G12S), synonymous ( SDHB A6A, SDHD ...
    www.ihop-net.org/UniPub/iHOP/gs/92076.html
  • Schmitt, AM (A M)
    Schmitt, AM (A M) :: Aerobic bacterial flora of oral and nasal fluids of canines with ... of amino-acid coding polymorphisms (S163P in SDHB connection as well as G12S and ...
    lib.bioinfo.pl/auid:2078535
  • EC 1.3.5.1 - succinate dehydrogenase (ubiquinone)
    Information on EC 1.3.5.1 - succinate dehydrogenase (ubiquinone) ... SDHA at chromosome band 5p15 and SDHB at chromosome band 1p35 encode the two catalytical ...
    brenda-enzymes.org/php/...&OrganismID=247&ShowAll=True
  • TNM staging of midgut and hindgut (neuro) endocrine tumors: a ...
    Loss of heterozygosity was found in 27%(SDHB) and 4%(SDHD) respectively. ... of amino-acid coding polymorphisms (S163P in SDHB SDHD as well as G12S and ...
    lib.bioinfo.pl/pmid:17674042

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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