SDHD H50R - GET-Evidence



(SDHD His50Arg)

Short summary

Probably benign. Other mutations in this gene are implicated in causing hereditary paraganglioma or pheochromocytoma syndromes, but this variant is also found in unaffected controls and is considered a nonpathogenic polymorphism by most authors that have reported it.

Variant evidence
Computational -
Functional -
Case/Control 2

Similar frequencies in cases and controls

See Cascon A et al. 2002 (12111639).


No familial data

Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Uncertain benign

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

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • G @ chr11:111958677: 0.7% (71/10758) in EVS
  • G @ chr11:111463886: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.7% (71/10758)


Cascon A, Ruiz-Llorente S, Cebrian A, Telleria D, Rivero JC, Diez JJ, Lopez-Ibarra PJ, Jaunsolo MA, Benitez J, Robledo M. Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. Eur J Hum Genet. 2002 Aug;10(8):457-61. PubMed PMID: 12111639.

Screening the SDHD gene for germline (inherited) mutations, these authors report seeing this variant once in set of 25 patients with phaeochromocytoma and/or paraganglioma tumours. They screened controls and found this in 4 out of 280 chromosomes — from this they concluded it is a polymorphism probably unrelated to the disease.

Perren A, Barghorn A, Schmid S, Saremaslani P, Roth J, Heitz PU, Komminoth P. Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients. Oncogene. 2002 Oct 24;21(49):7605-8. PubMed PMID: 12386824.

These authors find the polymorphism in one case and not in controls, but generally conclude that SDHD mutations are not playing a major role in this disease.

Korpershoek E, Petri BJ, van Nederveen FH, Dinjens WN, Verhofstad AA, de Herder WW, Schmid S, Perren A, Komminoth P, de Krijger RR. Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma. Endocr Relat Cancer. 2007 Jun;14(2):453-62. PubMed PMID: 17639058.

The authors observe this variant in two out of 23 patients but conclude that this frequency is similar to the frequency in controls reported by Cascon et al. and classify it as a nonpathogenic polymorphism.

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PubMed PMID: 18678321

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 SDHD 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.


hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het G @ chr11:111958677


Other external references

  • rs11214077
  • GeneTests records for the SDHD gene
    Hereditary Paraganglioma-Pheochromocytoma Syndromes
    SDHD-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome
  • Score: 0.995 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 6

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Gene search

"GENE" or "GENE A123C":

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