ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.343C>T (p.Arg115Ter) (rs751000085)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000178185 SCV000230200 pathogenic not provided 2015-05-04 criteria provided, single submitter clinical testing
Invitae RCV000627752 SCV000644757 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg115*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751000085, ExAC 0.003%). This variant has been reported in two families and several individuals affected with paraganglioma and/or pheochromocytoma (PMID: 16405730, 24523625, 25047027,21348866, 28490599). ClinVar contains an entry for this variant (Variation ID: 197210). Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000505340 SCV000711787 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2016-06-22 criteria provided, single submitter clinical testing The p.Arg115X variant in SDHB has been reported in at least two individuals with hereditary paragangliomas and pheochromocytomas and segregated with disease in 1 affected relative (Bayley 2006, Benn 2006, Lefebvre 2006). It has also been id entified in 2/66740 European chromosomes by the Exome Aggregation Consortium (Ex AC,; dbSNP rs751000085). This frequency is low en ough to be consistent with the frequency of hereditary paragangliomas and pheoch romocytomas in the general population. This nonsense variant is predicted to res ult in a premature termination codon at position 115, leading to a truncated or absent protein. Heterozygous loss-of-function variants in the SDHB gene are asso ciated with hereditary paragangliomas and pheochromocytomas. In summary, this va riant meets our criteria to be classified as pathogenic for hereditary paragangl iomas and pheochromocytomas in an autosomal dominant manner based on the predict ed impact to the protein and low frequency in controls.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505340 SCV001623275 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2021-05-11 criteria provided, single submitter clinical testing Variant summary: SDHB c.343C>T (p.Arg115X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251464 control chromosomes (gnomAD). c.343C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Bayley_2006, Benn_2006, Timmers_2007, Guan_2015, Richter_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV001507023 SCV001711958 pathogenic Paragangliomas 4 2021-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000178185 SCV001784301 pathogenic not provided 2021-05-14 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Identified in a patient with pheochromocytomas and paragangliomas in published literature (Bayley 2006, Benn 2006, Hensen 2012, Janssen 2015, Huang 2018, Richter 2019); This variant is associated with the following publications: (PMID: 32741965, 16405730, 16317055, 25873086, 21348866, 30352407, 30050099, 31447099, 31666924, 28490599, 25683602, 28503760, 17200167, 24523625, 25525159)
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505340 SCV000599499 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000178185 SCV001927548 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000178185 SCV001957643 pathogenic not provided no assertion criteria provided clinical testing

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