ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.590C>G (p.Pro197Arg) (rs74315367)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213984 SCV000273721 pathogenic Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing The p.P197R pathogenic mutation (also known as c.590C>G), located in coding exon 6 of the SDHB gene, results from a C to G substitution at nucleotide position 590. The proline at codon 197 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals/multiple families diagnosed with paragangliomas and/or pheochromocytomas (Astuti D et al. Am. J. Hum. Genet. 2001 Jul;69:49-54; Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Lawrence JK et al. Hormones (Athens) 2004. 3(2):127-31; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Jawed I et al. Cell. Mol. Neurobiol. 2018 Jul;38:1099-1106; Rijken JA et al. BJS Open. 2018 Apr;2:62-69), as well as an individual diagnosed with a GIST (Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11). In one study, PGL-PCC tumor studies of an individual known to carry the p.P197R alteration showed negative SDHB protein expression on IHC (van Nederveen FH et al. Lancet Oncol. 2009 Aug;10:764-71). Authors of one study showed that the p.P197R alteration led to mitochondrial expression levels and SDH enzyme activity levels similar to that of wild type cells in vitro; however structural modeling predicted this alteration would affect the function of the electron path in the electron transport chain (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Based on internal structural analysis, P197R introduces a large, positively-charged side-chain into a functionally critical region of SDHB, and is likely to disrupt both ubiquinone binding and reduction of ubiquinone (Sun F et al. Cell. 2005 Jul;121:1043-57; Yankovskaya V et al. Science. 2003 Jan;299:700-4; Guo J et al. J. Biol. Chem. 2003 Nov;278:47629-35). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this variant is also called p.P198R (c.724C>G) in some literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000465474 SCV000553988 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-05-23 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 197 of the SDHB protein (p.Pro197Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals and families affected with pheochromocytoma and/or paraganglioma (PMID: 18419787, 27542510, 25047027, 21348866, 29386252) and in an individual with gastrointestinal stromal tumor (PMID: 26556299). This variant has been reported to segregate with disease in 3 families with incomplete penetrance (PMID: 11404820, 18419787, 14974914). ClinVar contains an entry for this variant (Variation ID: 12779). Structural modeling based on human SDH predicts this variant may affect electron pathway (PMID: 25972245). However, experimental studies have shown that this missense change does not affect mitochondrial localization or protein function and behaves the same as wild-type in vitro (PMID: 25972245, 18519664, 28738844). In summary, this variant is a rare missense change that has been shown to preserve some aspects of protein function in vitro. However, this variant has also been observed in numerous affected individuals and segregates with disease in affected families. For these reasons, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001379 SCV001158579 likely pathogenic none provided 2019-11-12 criteria provided, single submitter clinical testing The SDHB c.590C>G; p.Pro197Arg variant (rs74315367) is reported in the literature in multiple individuals and families affected with hereditary paraganglioma/pheochromocytoma syndrome, though it has also been reported in several asymptomatic carriers (Astuti 2001, Lawrence 2004, Niemeijer 2017, Rijken 2018, Srirangalingam 2008). Another variant at this codon, p.Pro197Ser, is also reported in individuals with paragangliomas (Hermsen 2010, Lima 2007). The p.Pro197Arg variant is reported in ClinVar (Variation ID: 12779). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 197 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. While biochemical characterization of p.Pro197Arg variant protein showed no effect on SDH activity or association with SDHA protein, in silico analysis of this variant suggested defective electron transport and generation of reactive oxygen species (Kim 2015). Based on available information, the p.Pro197Arg variant is considered to be likely pathogenic. REFERENCES Astuti D et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001 Jul;69(1):49-54. Hermsen MA et al. Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management. Cell Oncol. 2010 Jan 1;32(4):275-83. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. Lawrence JK et al. Familial paraganglioma: a novel presentation of a case and response to therapy with radiolabelled MIBG. Hormones (Athens). 2004 Apr-Jun;3(2):127-31. Lima J et al. High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations. J Clin Endocrinol Metab. 2007 Dec;92(12):4853-64. Niemeijer ND et al. The phenotype of SDHB germline mutation carriers: a nationwide study. Eur J Endocrinol. 2017 Aug;177(2):115-125. Rijken JA et al. Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations. BJS Open. 2018 Feb 6;2(2):62-69. Srirangalingam U et al. Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. Clin Endocrinol (Oxf). 2008 Oct;69(4):587-96.
OMIM RCV000013617 SCV000033864 pathogenic Paragangliomas 4 2001-07-01 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030623 SCV000053301 not provided Hereditary Paraganglioma-Pheochromocytoma Syndromes 2015-10-02 no assertion provided clinical testing
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000030623 SCV000599521 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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