Submissions for variant NM_003000.3(SDHB):c.277T>C (p.Cys93Arg)

dbSNP: rs727503415

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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with paraganglioma (Lima 2007, Neumann 2009, Sevilla 2009, Hermsen 2010) and 1 individual with phe ochromocytoma (LMM unpublished data).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	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2022-11-13	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 93 of the SDHB protein (p.Cys93Arg). This missense change has been observed in individuals with paraganglioma and pheochromocytoma (PMID: 17848412, 19351833, 28374168, 31492822). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys93 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (PMID: 19258401, 27539324), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function. ClinVar contains an entry for this variant (Variation ID: 165180).
Myriad Genetics, Inc.	RCV003335134	SCV004042858	likely pathogenic	Paragangliomas 4	2023-04-25	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: 17848412, 32971818, 28646318, 31492822]. This variant is expected to disrupt protein structure [Myriad internal data].
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505315	SCV000599498	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research