Submissions for variant NM_003000.3(SDHB):c.286G>A (p.Gly96Ser)

gnomAD frequency: 0.00001  dbSNP: rs587782243

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130946	SCV000185859	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-03	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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459169	SCV000553993	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 96 of the SDHB protein (p.Gly96Ser). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs587782243, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of hereditary paraganglioma and/or pheochromocytoma syndrome (PMID: 2308387, 19802898, 24436918, 28374168, 29386252; external communications, internal data). ClinVar contains an entry for this variant (Variation ID: 142111). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000489952	SCV000577707	likely pathogenic	not provided	2025-03-26	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; 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, 34906457)
Revvity Omics, Revvity	RCV000489952	SCV002019156	likely pathogenic	not provided	2021-05-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474773	SCV004203035	likely pathogenic	Gastrointestinal stromal tumor	2022-09-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000505332	SCV004840105	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-11-14	criteria provided, single submitter	clinical testing	The c.286G>A (p.Gly96Ser) variant in the SDHB gene is located on the exon 3 and is predicted to replace glycine with serine at codon 96 (p.Gly96Ser). The variant has been reported in multiple individuals with paragangliomas/pheochromocytoma (PMID: 34906457, 19802898, 24436918, 28374168) and 2 unrelated individuals with renal cancer (PMID: 23083876, 28973655). The variant is predicted to cause splicing donor loss (SpliceAI delta score: 0.77), resulting in alternative splicing and disrupted protein product. Loss-of-function variants of SDHB are known to be pathogenic (PMID: 16258955, 19389109, 28490599). The variant is reported in ClinVar (ID: 142111). The variant is rare in the general population according to gnomAD (3/251244). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.967). Therefore, the c.286G>A (p.Gly96Ser) variant of SDHB has been classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004019743	SCV004933688	likely pathogenic	Paragangliomas 4	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23083876, 24436918, 30201732, 34906457, 29386252].
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505332	SCV000599493	likely pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research