Submissions for variant NM_003000.2(SDHB):c.725G>A (p.Arg242His) (rs74315368)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129095	SCV000183806	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-14	criteria provided, single submitter	clinical testing	The p.R242H pathogenic mutation (also known as c.725G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at nucleotide position 725. The arginine at codon 242 is replaced by histidine, an amino acid with highly similar properties. The p.R242H mutation has been well described in published literature. It has been identified in numerous individuals with tumors across the paraganglioma-pheochromocytoma (PGL-PCC) syndrome spectrum, including thoracic, pelvic, and head and neck PGL, adrenal PCC, and renal cell carcinoma (Neumann HP et al. JAMA. 2004 Aug;292:943-51; Ghayee HK et al. Endocr. Relat. Cancer. 2009 Mar;16:291-9; Luiz HV et al. Pediatrics. 2013 Dec;32:e1709-14; Persu A et al. J. Hypertens. 2008 Jul;26:1395-401; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Merlo A et al. J. Clin. Endocrinol. Metab 2013 Oct;98:E1661-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; van Hulsteijn LT et al. Fam. Cancer. 2014 Dec;13:651-7; Janssen I et al. Clin. Cancer Res. 2015 Sep;21:3888-95; Gill AJ et al. Am. J. Surg. Pathol. 2014 Dec;38:1588-602). In one study, mutant yeast strains with this mutation showed a significant defect and structural analysis suggested that this mutation alters the conformation of the protein, causing a decrease in the positive surface extent of the mutant protein (Nesti C et al. Hum. Mol. Genet. 2015 Jun;24:3248-56). Additionally, structural modeling of this mutation has predicted disruption of the electron path and impaired functional activity (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Of note, two different alterations at the same codon, p.R242C and p.R242S, have also been reported in patients with head/neck PGLs and PCCs (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22:804-15; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Lefebvre S et al. Horm. Metab. Res. 2012 May;44:334-8; Badenhop RF et al. J. Med. Genet. 2004 Jul;41:e99). Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000183216	SCV000235636	pathogenic	not provided	2019-01-09	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted SDHB c.725G>A at the cDNA level, p.Arg242His (R242H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been reported in a father and son with malignant paragangliomas, several individuals with both malignant and benign paraganglioma/ pheochromocytoma tumors, a young adult with a gastrointestinal stromal tumor, and a patient with an SDHB-deficient renal carcinoma (Young 2002, Neumann 2004, Persu 2008, Cascon 2009, Ghayee 2009, Sevilla 2009, Janeway 2011, Luiz 2013, Gill 2014, Rijken 2017). SDHB Arg242His was also observed in a patient with clinical and metabolic features suggestive of a mitochondrial disorder, for whom assays to interrogate mitochondrial dysfunction in cultured fibroblasts and muscle tissue revealed reduced complex II and III activities and SDHA and SDHB expression (Nesti 2015). While this patient also harbored a heteroplasmic MT-CYB variant which might have contributed to these laboratory findings, yeast-based assays interrogating each variant separately only found decreased complex II and III activities for the strain expressing the yeast corollary of SDHB Arg242His (Nesti 2015). Additionally, Kim et al. (2015) found SDHB Arg242His to significantly reduce SDH activity, while Dwight et al. (2017) demonstrated this variant to completely abrogate SDHAF3 interaction. SDHB Arg242His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in an L(I)YR motif required for interaction with Fe-S cluster transfer machinery and acquisition (Maio 2014, Saxena 2015). 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	RCV000627751	SCV000644767	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2020-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 242 of the SDHB protein (p.Arg242His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs74315368, ExAC 0.01%). This variant has been observed in several individuals and families affected with sporadic and familial hereditary paragangliomas and/or pheochromocytomas (PMID: 12000816, 20208144, 24276837, 12213855, 17102084, 22270996), gastrointestinal stromal tumors (PMID: 21173220), and mitochondrial encephalomyopathy (PMID: 25736212). ClinVar contains an entry for this variant (Variation ID: 12781). Experimental studies using a model organism have shown that this variant causes deleterious effects on several aspects of protein function (PMID: 25972245, 25736212, 22835832). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000013619	SCV001367997	pathogenic	Paragangliomas 4	2019-04-17	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.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000183216	SCV001746833	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
OMIM	RCV000013619	SCV000033866	pathogenic	Paragangliomas 4	2011-01-04	no assertion criteria provided	literature only
OMIM	RCV000013620	SCV000033867	pathogenic	Pheochromocytoma	2011-01-04	no assertion criteria provided	literature only
OMIM	RCV000022778	SCV000044067	pathogenic	Gastrointestinal stromal tumor	2011-01-04	no assertion criteria provided	literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health	RCV000505354	SCV000599525	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes		no assertion criteria provided	research