ClinVar Miner

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

gnomAD frequency: 0.00185  dbSNP: rs111430410
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Total submissions: 17
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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).

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