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 likely pathogenic Hereditary cancer-predisposing syndrome 2016-11-23 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000465474 SCV000553988 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-05-30 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 not specified 2018-07-13 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 a several asymptomatic carriers (Astuti 2001, Lawrence 2004, Srirangalingam 2008). This variant is reported in ClinVar (Variation ID: 12779) and is found in the general population with an overall allele frequency of 0.0004% (1/245986 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon, p.Pro197Ser, has been reported in individuals with paragangliomas (Hermsen 2010, Lima 2007). 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, attributes not explicitly tested in the assays run (Kim 2015). The proline at codon 197 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this 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. 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
Integrated Genetics/Laboratory Corporation of America 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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