Submissions for variant NM_003000.3(SDHB):c.725G>A (p.Arg242His)

gnomAD frequency: 0.00001  dbSNP: rs74315368

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129095	SCV000183806	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-08	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	2023-01-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced SDH/complex II activity and abrogated SDHAF3 interaction (Kim et al., 2015; Nesti et al., 2015; Dwight et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12213855, 19393419, 23433498, 25025441, 17102084, 29925701, 34906457, 32782288, 24606901, 22835832, 25736212, 12000816, 25972245, 21173220, 20208144, 22293219, 19258401, 17652212, 19802898, 22270996, 25047027, 19454582, 18551016, 28374168, 25899001, 27573198, 15328326, 24276837, 25873086, 19075037, 16317055, 28503760, 29386252, 29204718, 29951630, 29800631, 29950348, 28748451, 31212687, 30549360, 31104306, 30658386, 28490599, 31492822, 30050099, 26464466, 31589614, 32741965, 33644666, 30787465, 28738844)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627751	SCV000644767	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 242 of the SDHB protein (p.Arg242His). This variant is present in population databases (rs74315368, gnomAD 0.007%). This missense change has been observed in individuals with sporadic and familial hereditary paragangliomas and/or pheochromocytomas (PMID: 12000816, 12213855, 17102084, 20208144, 21173220, 22270996, 24276837, 25736212). ClinVar contains an entry for this variant (Variation ID: 12781). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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, 25736212, 25972245). This variant disrupts the p.Arg242 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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.
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 Center for Human Genetics Tuebingen	RCV000183216	SCV001746833	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000183216	SCV002010041	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
DASA	RCV001836632	SCV002097298	pathogenic	SDHB-related disorder	2022-02-14	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 25972245; 25736212; 22835832) - PS3. The c.725G>A;p.(Arg242His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12781; OMIM: 185470.0004; PMID: 12000816; 20208144; 24276837; 12213855; 17102084; 22270996) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Fer4) - PM1. This variant is not present in population databases (rs7431536, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 239443 - c.724C>A (p.Arg242Ser); ClinVar ID: 186827 - c.724C>T (p.Arg242Cys)) - PM5. Missense variant in SDHB that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is pathogenic.
Sema4, Sema4	RCV000129095	SCV002527089	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000013619	SCV002580428	pathogenic	Paragangliomas 4	2021-10-05	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000505354	SCV002761484	pathogenic	Hereditary pheochromocytoma-paraganglioma	2020-11-10	criteria provided, single submitter	clinical testing	The SDHB c.725G>A variant is a single nucleotide substitution from a guanine to an adenonine at position 725 which is predicted to change the arginine at position 242 in the protein to histidine. The variant has been reported multiple times in the literature in association with disease (PMID: 12000816, 12213855, 15328326, 28490599) (PS1). Functional studies demonstrate that the variant has a detrimental effect on protein function (PMID: 25972245, 22835832) (PS3). The variant is listed in dbSNP (rs74315368) and is rare in population databases (gnomAD 3 het/251,440 total, 0 hom). The variant is described in ClinVar as pathogenic (ClinVar ID: 27820) and HGMD (2020.3) as disease causing (PP5). Computational predictions support a deleterious effect on the gene or gene product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505354	SCV003929309	pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.725G>A (p.Arg242His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251440 control chromosomes. c.725G>A has been reported in the literature in multiple individuals affected with features of Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Persu_2008, Amar_2007, Young_2002, Benn_2006, Neumann_2004, Neumann_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12000816, 17652212, 16317055, 15328326, 18551016, 12213855). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000022778	SCV004203045	pathogenic	Gastrointestinal stromal tumor	2021-08-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000183216	SCV004220335	pathogenic	not provided	2013-06-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/251440 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals affected with PGL-PCC syndrome (PMID: 12000816 (2002), 12213855 (2002), 18551016 (2008), 19351833 (2009), 29386252 (2018), 34439168 (2021), 34906457 (2022)). Functional studies observed decreased stability of the SDHB protein (PMID: 22835832 (2012)) and a severe decrease in succinate dehydrogenase activity (PMID: 25736212 (2015), 25972245 (2015)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000183216	SCV004563897	pathogenic	not provided	2023-08-02	criteria provided, single submitter	clinical testing	The SDHB c.725G>A; p.Arg242His variant (rs74315368) is reported in the literature in individuals affected with paraganglioma or pheochromocytoma (Luiz 2013, Neumann 2002, Neumann 2009, Niemeijer 2017, Young 2002). In at least one family, this variant was observed to segregate with disease (Young 2002). This variant is also reported in ClinVar (Variation ID: 12781). It is only found on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.944). Consistent with these predictions, functional assays have observed that this variant exhibits decreased SDH/complex II activity (Kim 2015, Nesti 2015) and increased ubiquitination (Yang 2012). Additionally, other amino acid substitutions at this codon (p.Arg242Cys, p.Arg242Ser) have been reported in individuals with paraganglioma and are considered pathogenic (Badenhop 2004, Neumann 2009). Based on available information, the p.Arg242His variant is considered to be pathogenic. References: Badenhop RF et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet. 2004 Jul;41(7):e99. PMID: 15235042. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. PMID: 25972245. Luiz HV et al. Malignant paraganglioma presenting with hemorrhagic stroke in a child. Pediatrics. 2013 Dec;132(6):e1709-14. PMID: 24276837. Nesti C et al. Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy. Hum Mol Genet. 2015 Jun 1;24(11):3248-56. PMID: 25736212. Neumann HP et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009 Apr 15;69(8):3650-6. PMID: 19351833. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 May 9;346(19):1459-66. PMID: 12000816. Niemeijer ND et al. The phenotype of SDHB germline mutation carriers: a nationwide study. Eur J Endocrinol. 2017 Aug;177(2):115-125. PMID: 28490599. Yang C et al. Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function. FASEB J. 2012 Nov;26(11):4506-16. PMID: 22835832. Young AL et al. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. J Clin Endocrinol Metab. 2002 Sep;87(9):4101-5. PMID: 12213855.
Myriad Genetics, Inc.	RCV000013619	SCV004933620	likely pathogenic	Paragangliomas 4	2024-02-08	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: 30050099, 32462735, 33362715, 34439168]. This variant is expected to disrupt protein structure [Myriad internal data].
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786257	SCV005399928	pathogenic	Mitochondrial complex 2 deficiency, nuclear type 4	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex II deficiency, nuclear type 4 (MIM#619224), pheochromocytoma (MIM#171300) and paragangliomas 4 (MIM#115310). (I) 0108 - This gene is associated with both recessive and dominant disease. However, the genotype-phenotype correlation is currently unestablished (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 4Fe-4S dicluster domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several individuals with pheochromocytoma (MIM#171300) and/or paragangliomas 4 (MIM#115310), rarely in non-paraganglioma tumours such as gastrointestinal stromal tumour and a single case of mitochondrial encephalomyopathy (PMID: 32460727, 33748650, 28490599, 21173220, 25736212). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
All of Us Research Program, National Institutes of Health	RCV000505354	SCV005424049	pathogenic	Hereditary pheochromocytoma-paraganglioma	2024-08-08	criteria provided, single submitter	clinical testing	The c.725G>A variant in the SDHB gene is located on the exon 7 and is predicted to replace arginine with histidine at codon 242 (p.Arg242His). The variant has been reported in multiple unrelated individuals with paraganglioma/pheochromocytoma/renal cell carcinoma (PMID: 12000816, 32661476, 33748650, 36597280, 29925701, 33362715, 34906457). Alternative variants disrupting the same amino acid (p.Arg242Ser, p.Arg242Cys) have been interpreted as pathogenic (ClinVar ID: 239443, 186827). In vitro SDH activity assay and co-immunoprecipitation experiment in mammalian cells demonstrated impaired function and abolished interaction with the SDH aseembly factor SDHAF3 (PMID: 25972245, 28738844). The variant is reported in ClinVar (ID: 12781). The variant is rare in general population according to gnomAD (18/1613846 chromosomes, 0.001%) . Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.94). Therefore, the c.725G>A (p.Arg242His) variant in the SDHB gene is classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001836632	SCV005900598	pathogenic	SDHB-related disorder	2024-08-14	criteria provided, single submitter	clinical testing	The c.725G>A (p.Arg242His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in patients with hereditary paraganglioma-pheochromocytoma syndromes (PMID: 12000816, 12213855, 20208144, 21173220, 24276837, 25736212). The c.725G>A (p.Arg242His) variant is located in a mutational hotspot for pathogenic variations associated with hereditary paraganglioma-pheochromocytoma syndromes (PMID: 23175444, 15235042). Functional studies demonstrated that the c.725G>A (p.Arg242His) variant results in decreased stability of the SDHB protein and a severe decrease in succinate dehydrogenase activity (PMID: 25972245, 22835832, 25736212).The c.725G>A (p.Arg242His) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.001% (18/1613846) and thus is presumed to be rare. Based on the available evidence, c.725G>A (p.Arg242His) is classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000505354	SCV006060934	pathogenic	Hereditary pheochromocytoma-paraganglioma	2024-10-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 242 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Experimental functional studies have demonstrated the variant decreased succinate dehydrogenase enzyme activity and altered the conformation of the SDHB protein, lowering it protein stability (PMID: 22835832, 25736212, 25972245). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma (PMID: 12000816, 12213855, 15328326, 18551016, 19075037, 19351833, 19454582, 20208144, 22270996, 23666964, 23902947, 24276837, 25047027, 25873086, 28490599, 29386252, 29951630). This variant has been identified in 3/251440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000013619	SCV000033866	pathogenic	Paragangliomas 4	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 pheochromocytoma-paraganglioma		no assertion criteria provided	research