ClinVar Miner

Submissions for variant NM_003000.3(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
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with paraganglioma (Lima 2007, Neumann 2009, Sevilla 2009, Hermsen 2010) and 1 individual with phe ochromocytoma (LMM unpublished data).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.
Ambry Genetics RCV000572682 SCV000664570 pathogenic Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing The p.C93R pathogenic mutation (also known as c.277T>C), located in coding exon 3 of the SDHB gene, results from a T to C substitution at nucleotide position 277. The cysteine at codon 93 is replaced by arginine, an amino acid with highly dissimilar properties. This pathogenic variant has been identified in several individuals diagnosed with paragangliomas (Lima J et al. J. Clin. Endocrinol. Metab. 2007 Dec;92:4853-64; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in loss of protein domain function (Inaoka DK et al. Int J Mol Sci. 2015 Jul;16(7):15287-308). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000798906 SCV000938549 uncertain significance Gastrointestinal stromal 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.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505315 SCV000599498 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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