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

Total submissions: 9

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