Submissions for variant NM_003000.3(SDHB):c.688C>T (p.Arg230Cys)

gnomAD frequency: 0.00001  dbSNP: rs138996609

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164435	SCV000215074	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	The p.R230C pathogenic mutation (also known as c.688C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 688. The arginine at codon 230 is replaced by cysteine, an amino acid with highly dissimilar properties. This pathogenic variant has been reported in numerous individuals diagnosed with pheochromocytomas and/or paragangliomas (Gimenez-Roqueplo AP et al. Cancer Res. 2003 Sep 1;63(17):5615-21; Dahia PL et al. PLoS Genet. 2005 Jul;1(1):72-80; Neumann HP et al. Cancer Res. 2009 Apr 15;69(8):3650-6; Sevilla MA et al. Otolaryngol Head Neck Surg. 2009 May;140(5):724-9; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Yang C et al. FASEB J. 2012 Nov;26(11):4506-16; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). Additionally, two disease-causing variants, p.R230H and p.R230L, have been described in the same codon. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000520697	SCV000617569	pathogenic	not provided	2017-10-05	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted SDHB c.688C>T at the cDNA level, p.Arg230Cys (R230C) at theprotein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in severalindividuals with pheochromocytoma or paraganglioma (Gimenez-Roqueplo 2003, Lefebvre 2012, Hermsen 2010,Janssen, Jochmanova 2017). In addition, functional assays have demonstrated this variant to result in an unstableprotein, and in the tumor of an individual harboring this variant, complete and selective loss of mitochondrial complex IIenzyme activity was observed (Yang 2012, Gimenez-Roqueplo 2003). SDHB Arg230Cys was not observed at asignificant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity,charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHB Arg230Cysoccurs at a position that is conserved across species and is not located in a known functional domain. In silicoanalyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currentlyavailable evidence, we consider this variant to be pathogenic
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528137	SCV000644765	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-04-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 230 of the SDHB protein (p.Arg230Cys). This variant is present in population databases (rs138996609, gnomAD 0.0009%). This missense change has been observed in individuals with malignant or non-malignant pheochromocytoma or paraganglioma (PMID: 14500403, 17652212, 19454582, 20208144, 22517554, 25873086). ClinVar contains an entry for this variant (Variation ID: 185077). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832). This variant disrupts the p.Arg230 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18382370, 19351833, 23934599; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660258	SCV000782279	pathogenic	Paragangliomas 4	2016-11-01	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000660258	SCV000840068	pathogenic	Paragangliomas 4	2018-01-14	criteria provided, single submitter	clinical testing	The c.688C>T (p.Arg230Cys) variant in the SDHB gene has been reported in several unrelated individuals with pheochromocytoma or paraganglioma (PMID: 14500403, 24939699, 20208144, and 28374168). Functional assays have demonstrated that this missense change results in an unstable protein, and in the tumor of an individual with this variant complete and selective loss of mitochondrial complex II enzyme activity was observed (PMID: 22835832, 14500403). Additionally, two other pathogenic/likely pathogenic missense substitutions at this codon have been reported (PMID: 22835832, 23934599, 18382370, and 19351833,) suggesting that the Arg230 residue is critical for normal functioning of the SDHB protein. In light of the currently available data this variant in the SDHB gene is classified pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000660258	SCV001369396	pathogenic	Paragangliomas 4	2020-01-06	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3.
Myriad Genetics, Inc.	RCV000660258	SCV004017902	likely pathogenic	Paragangliomas 4	2023-02-08	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: 14500403, 33362715, 28374168, 34906457]. This variant is expected to disrupt protein structure [Myriad internal data].
All of Us Research Program, National Institutes of Health	RCV000505374	SCV004821938	pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 230 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant may impact protein stability and increase SDHB ubiquitination (PMID: 14500403, 22835832, 35673401). This variant has been reported in individuals affected with pheochromocytomas, paragangliomas, and gastrointestinal stromal tumors (PMID: 16103922, 17652212, 19351833, 19454582, 20208144, 22517554, 25873086, 29386252, 30536464, 34906457, 33420946, 35673401, 35904169). Other amino acid changes at this codon are considered disease causing (R230L, R230H, R230G; ClinVar Variant IDs: 184933, 142637, 1755980). This variant has been identified in 2/251398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505374	SCV000599523	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research