ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.287G>A (p.Gly96Asp) (rs778952116)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492591 SCV000581190 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing The p.G96D variant (also known as c.287G>A) is located in coding exon 4 of the SDHB gene. The glycine at codon 96 is replaced by aspartic acid, an amino acid with similar properties. This variant is located in the 2Fe-2S iron-sulfur cluster binding domain and has been reported in numerous individuals with paragangliomas and pheochromocytomas (Timmers HJ et al. J Clin Endocrinol Metab. 2008 Dec;93(12):4826-32; Benn DE et al. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36; Samuel N et al. J Surg Oncol, 2018 Feb;117:160-162; Ghayee HK et al. Endocr. Relat. Cancer, 2009 Mar;16:291-9; Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000633945 SCV000755218 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-08-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 96 of the SDHB protein (p.Gly96Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs778952116, ExAC 0.001%). This variant has been reported in several individuals affected with pheochromocytoma or paraganglioma (PMID: 16317055, 17538171, 19075037). ClinVar contains an entry for this variant (Variation ID: 428916). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660255 SCV000782274 pathogenic Paragangliomas 4 2016-11-01 criteria provided, single submitter clinical testing
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505304 SCV000599501 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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