Total submissions: 3
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 |
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. |
Gene |
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) |