ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.277T>C (p.Cys93Arg) (rs727503415)

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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 RCV000572682 SCV000664570 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-25 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Invitae RCV000798906 SCV000938549 uncertain significance Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-07-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 93 of the SDHB protein (p.Cys93Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with paraganglioma in the literature (PMID: 17848412, 19351833) and the Leiden Open-source Variation Database (PMID: 21520333). However, there was no evidence of segregation with disease reported for one of these families (PMID: 17848412). ClinVar contains an entry for this variant (Variation ID: 165180). 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151828 SCV000200298 uncertain significance not specified 2015-08-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys93Arg variant in SDHB has been previously reported in 4 individuals with paraganglioma (Lima 2007, Neumann 2009, Sevilla 2009, Hermsen 2010) and 1 individual with phe ochromocytoma (LMM unpublished data). It was also identified in 2 reportedly un affected family members (Lima 2007), though this could be due to reduced penetra nce and/or age of onset. It was absent from large population studies. Computatio nal prediction tools and conservation analyses, including structural analyses, s uggest this variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In summary, while there is some suspici on for a pathogenic role, the clinical significance of the Cys93Arg variant is u ncertain.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505315 SCV000599498 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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