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

gnomAD frequency: 0.00185  dbSNP: rs111430410

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000607044	SCV000053116	likely benign	not specified	2021-02-05	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 0.00054 in 274908 control chromosomes, predominantly at a frequency of 0.0055 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 629 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHB causing Pheochromocytoma phenotype (8.8e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.32G>A has been reported in the literature in at least an individual affected with adrenal Pheochromocytoma. However, the authors classified the variant as likely benign based on normal succinate: fumarate ratio obtained from a mass spectrometry-based screening assay performed on patient derived tissue samples (Richter_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232749	SCV000287771	benign	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-02-01	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001731321	SCV000730538	likely benign	not provided	2021-09-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24092654, 28374168, 24055113, 25637381, 26332594, 22835832, 18728283, 19576851, 30050099)
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)
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV002250465	SCV002521907	benign	Pheochromocytoma	2022-03-11	criteria provided, single submitter	clinical testing	Data included in classification: Allele frequency is above 1x10-4 in gnomAD (77/14092 alleles in African population, MAF 0.5%, 92/114849 = MAF of 0.08% across all populations in gnomAD) (BA1_SA) Data not included in classification: Revel score 0.627 Observed in 3 UK probands with phaeochromocytoma/paraganglioma, one of which head and neck. Also observed in UK proband with 3 renal carcinomas, all with loss of SDHB on IHC
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV002250466	SCV002521908	benign	Paraganglioma	2022-03-11	criteria provided, single submitter	clinical testing	Data included in classification: Allele frequency is above 1x10-4 in gnomAD (77/14092 alleles in African population, MAF 0.5%, 92/114849 = MAF of 0.08% across all populations in gnomAD) (BA1_SA) Data not included in classification: Revel score 0.627 Observed in 3 UK probands with phaeochromocytoma/paraganglioma, one of which head and neck. Also observed in UK proband with 3 renal carcinomas, all with loss of SDHB on IHC
Sema4, Sema4	RCV000568010	SCV002527070	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000607044	SCV002774048	benign	not specified	2022-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477028	SCV002802466	likely benign	Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma; Mitochondrial complex 2 deficiency, nuclear type 4	2022-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662963	SCV004045354	uncertain significance	Paragangliomas 4	2023-04-24	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607044	SCV004847567	benign	not specified	2020-08-10	criteria provided, single submitter	clinical testing	The p.Arg11His variant in SDHB is classified as benign because it has high allele frequency. Although, ithas been reported in 1 individual with bilateral renal cell carcinoma (Ricketts 2008 PMID: 18728283), 1 individual with a neuroendocrine tumor but whose tumor was positive for SDHB immunostaining (van Nederveen 2009 PMID: 19576851), and classified as a VUS by Amendola (2015 PMID: 25637381) and Dorschner (2013 PMID: 24055113), it was also identified in 0.55% (133/24062) African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 36768). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BA1, BS4.
CSER _CC_NCGL, University of Washington	RCV000148868	SCV000190612	uncertain significance	Papillary renal cell carcinoma type 1	2014-06-01	no assertion criteria provided	research
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505348	SCV000599482	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004532428	SCV004725049	likely benign	SDHB-related disorder	2019-10-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).