ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.32G>A (p.Arg11His) (rs111430410)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000607044 SCV000053116 likely benign not specified 2018-03-02 criteria provided, single submitter clinical testing Variant summary: SDHB c.32G>A (p.Arg11His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 104928 control chromosomes. The observed variant frequency is approximately 544 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHB causing Pheochromocytoma phenotype (8.8e-07), strongly suggesting that the variant is benign. c.32G>A has been reported in the literature in individuals affected with eosinophilic chromophobe renal cell carcinoma. These report(s) do not provide unequivocal conclusions about association of the variant with Pheochromocytoma. One publication reports experimental evidence indicating positive SDHB immunostaining in tumors harboring this variant without concommitant pathogenic SDH-gene mutations. However, this does not allow convincing conclusions about the variant effect. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000232749 SCV000287771 benign Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-12-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568010 SCV000675059 likely benign Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing Other data supporting benign classification;In silico models in agreement (benign);Subpopulation frequency in support of benign classification
GeneDx RCV000607044 SCV000730538 likely benign not specified 2018-02-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000662963 SCV000785936 likely benign Paragangliomas 4 2018-01-16 criteria provided, single submitter clinical testing
Mendelics RCV000986269 SCV001135208 likely benign Gastrointestinal stromal tumor 2019-05-28 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001253761 SCV001429630 likely benign Pheochromocytoma; Paraganglioma 2020-07-10 criteria provided, single submitter clinical testing This variant has been observed in a 52-year-old proband diagnosed with three primary renal cell carcinomas, bilateral disease, multiple renal cysts and single angiomyolipoma. This variant has also been observed in three unrelated (to our knowledge) diagnostic cases of PP/PGL (one of which has inner ear PGL). This variant has previously been reported in the literature in patients with bilateral renal cell carcinoma (PMID: 18728283) and neuroendocrine tumour (PMID: 19576851). Succinate:Fumarate ratio in tumour samples from a patient with this variant were observed to be within normal range, indicating neutral impact on protein function (PMID: 30050099) (BS3_supporting). This variant has been observed in 149/274308 total alleles in gnomAD; including 133/24062 African alleles (BS1_strong). Data included in classification: Functional data and control (gnomAD) data Data not included in classification: Incidence in literature and other reported probands In silico predictions (conflicting)
CSER _CC_NCGL, University of Washington RCV000148868 SCV000190612 uncertain significance Renal cell carcinoma, papillary, 1 2014-06-01 no assertion criteria provided research
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505348 SCV000599482 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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