ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.286G>A (p.Gly96Ser) (rs587782243)

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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 RCV000130946 SCV000185859 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000489952 SCV000577707 likely pathogenic not provided 2018-02-22 criteria provided, single submitter clinical testing This variant is denoted SDHB c.286G>A at the cDNA level, p.Gly96Ser (G96S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has been reported in multiple individuals with paraganglioma/pheochromocytoma, and in two affected members of a familial renal cell carcinoma kindred (Ricketts 2010, Ricketts 2012, Sridhara 2013, Jochmanova 2017, Andrews 2018). SDHB Gly96Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the 2Fe-2S ferredoxin-type domain (Uniprot). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect.? In addition, multiple splicing models predict that this variant may damage the nearby natural splice donor site.? However, in the absence of RNA or functional studies, the actual effect of this variant is unknown.? Based on currently available evidence, we consider SDHB Gly96Ser to be a likely pathogenic variant.
Invitae RCV000459169 SCV000553993 likely pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 96 of the SDHB protein (p.Gly96Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. It also falls at the last nucleotide of exon 3 of the SDHB coding sequence. This variant is present in population databases (rs587782243, ExAC <0.01%). This variant has been reported in individuals affected with paraganglioma (PMID: 24436918, Invitae), at least one individual with increased risk of pheochromocytoma or head and neck paraganglioma (PMID: 1980289), and in two individuals affected with renal cell carcinoma from a single family (PMID: 2308387). ClinVar contains an entry for this variant (Variation ID: 142111). 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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505332 SCV000599493 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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