ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.296G>A (p.Gly99Asp)

dbSNP: rs878854576
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492765 SCV000581205 likely pathogenic Hereditary cancer-predisposing syndrome 2024-06-17 criteria provided, single submitter clinical testing The p.G99D variant (also known as c.296G>A), located in coding exon 4 of the SDHB gene, results from a G to A substitution at nucleotide position 296. The glycine at codon 99 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been identified in multiple individuals with personal and/or family history of paraganglioma and/or pheochromocytoma (Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Andrews KA et al. J Med Genet, 2018 06;55:384-394; Bayley JP et al. J Med Genet, 2020 02;57:96-103). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001377867 SCV001575312 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2024-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 99 of the SDHB protein (p.Gly99Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma and/or pheochromocytoma (PMID: 16317055, 31492822; internal data). ClinVar contains an entry for this variant (Variation ID: 239428). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV002510827 SCV002820387 likely pathogenic not provided 2022-07-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with paraganglioma and/or pheochromocytoma (Benn et al., 2006; Andrews et al., 2018; Bayley et al., 2020); This variant is associated with the following publications: (PMID: 15989954, 16317055, 29386252, 33162331, 19802898, 25972245, 19215943, 31492822, 29315604)

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