ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.689G>A (p.Arg230His) (rs587782604)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Academic Department of Medical Genetics, University of Cambridge RCV000131970 SCV000992188 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Ambry Genetics RCV000131970 SCV000187028 pathogenic Hereditary cancer-predisposing syndrome 2018-02-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Center for Human Genetics, Inc RCV000660259 SCV000782280 pathogenic Paragangliomas 4 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762865 SCV000893245 pathogenic Paraganglioma and gastric stromal sarcoma; Paragangliomas 4; Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000183215 SCV000235635 pathogenic not provided 2018-09-25 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHB c.689G>A at the cDNA level, p.Arg230His (R230H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). SDHB Arg230His has been observed in several individuals and families with early-onset, multifocal, and/or malignant paragangliomas/pheochromocytomas as well as renal cell carcinomas, with several tumors demonstrating loss of SDHB protein expression via immunohistochemistry (Amar 2005, Brouwers 2006, Timmers 2007, Said-Al-Naief 2008, Burnichon 2009, Cascon 2009, van Nederveen 2009, Cerecer-Gil 2010, Xekouki 2015, Andrews 2018). This variant has also been reported in the compound heterozygous state in an individual with complex II deficiency with leukoencephalopathy (Gr?nborg 2016). SDHB Arg230His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000456660 SCV000554030 pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 230 of the SDHB protein (p.Arg230His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with pheochromocytomas, paragangliomas and renal cell carcinomas (PMID: 17200167, 20614293, 23083876, 24509376, 25695889, 26259135, 27539324), and was shown to segregate with disease in two families (PMID: 20592014 and Invitae database). ClinVar contains an entry for this variant (Variation ID: 142637). 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. Two additional missense substitutions at this codon (p.Arg230Cys, p.Arg230Leu) have been determined to be pathogenic (PMID: 14500403, 16314641, 18382370, 19351833, 27539324, 24939699, Invitae database). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505312 SCV000599524 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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