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 pathogenic Hereditary cancer-predisposing syndrome 2020-06-01 criteria provided, single submitter clinical testing The p.G96S pathogenic mutation (also known as c.286G>A), located in coding exon 3 of the SDHB gene, results from a G to A substitution at nucleotide position 286. This change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glycine at codon 96 to serine, an amino acid with similar properties. This variant has been identified in multiple affected individuals with SDHB-associated tumors (Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435; Sridhara SK et al. J Neurol Surg B Skull Base, 2013 Aug;74:236-40; Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71; Ricketts CJ et al. Hum Mutat. 2010 Jan;31(1):41-51; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000459169 SCV000553993 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-06 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 with clinical features of hereditary paraganglioma and/or pheochromocytoma syndrome (PMID: 19802898, 24436918, 29386252, 2308387, 28374168, Invitae). Also, it has been observed 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.
GeneDx RCV000489952 SCV000577707 likely pathogenic not provided 2021-04-16 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31579262, 24436918, 28973655, 29386252, 25972245, 26273102, 28152038, 28374168, 19802898, 23083876, 33300499, 32741965)
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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