ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.296G>A (p.Gly99Asp) (rs878854576)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232854 SCV000287768 likely pathogenic Paragangliomas 4 2017-04-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 99 of the SDHB protein (p.Gly99Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with paraganglioma (PMID: 16317055). It has also been observed in several other individuals affected with paraganglioma/pheochromocytoma in the Invitae database. ClinVar contains an entry for this variant (Variation ID: 239428). This variant, located in a conserved region of the SDHB protein involved in creating an iron-sulfur binding pocket, was predicted by crystal structure-based in silico analyses to affect the electron pathways of the protein or lead to impaired protein stability (PMID: 25972245, 19802898, 15989954). Additional 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 none of these predictions have been confirmed by published functional studies. In summary, this variant is a rare variant that is absent in the population, has been reported in several affected individuals, and falls within a conserved region of SDHB that is important for protein stability. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000492765 SCV000581205 likely pathogenic Hereditary cancer-predisposing syndrome 2015-10-05 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 a few similar properties.<span style="background-color:initial">The p.G99D variant was previously reported in an individual diagnosed with an abdominal paraganglioma and metastases at age 48 years (Benn DE et al. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36).<span style="background-color:initial">This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13,006 alleles) with coverage at this position.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.04% (greater than 10000alleles tested) in our clinical cohort.<span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.<span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001377867 SCV001575312 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-07-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 99 of the SDHB protein (p.Gly99Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with paraganglioma (PMID: 16317055). It has also been observed in several other individuals affected with paraganglioma/pheochromocytoma in the Invitae database. ClinVar contains an entry for this variant (Variation ID: 239428). This variant, located in a conserved region of the SDHB protein involved in creating an iron-sulfur binding pocket, was predicted by crystal structure-based in silico analyses to affect the electron pathways of the protein or lead to impaired protein stability (PMID: 25972245, 19802898, 15989954). Additional 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 none of these predictions have been confirmed by published functional studies. In summary, this variant is a rare variant that is absent in the population, has been reported in several affected individuals, and falls within a conserved region of SDHB that is important for protein stability. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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