ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.380T>G (p.Ile127Ser) (rs786201095)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162628 SCV000213063 pathogenic Hereditary cancer-predisposing syndrome 2018-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),Well-characterized mutation at same position
GeneDx RCV000505708 SCV000235631 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing This variant is denoted SDHB c.380T>G at the cDNA level, p.Ile127Ser (I127S) at the protein level, and results in the change of an Isoleucine to a Serine (ATC>AGC). This variant has been observed in multiple individuals with a personal history of pheochromocytoma, paraganglioma, gastrointestinal stromal tumor, and/or renal cell carcinoma (Benn 2006, Bolland 2006, Brouwers 2006, Meyer-Rochow 2009, Collins 2012, Miettinen 2013, Martucci 2015, Sue 2015, Casey 2017, Jochmanova 2017, Andrews 2018). While functional studies have demonstrated that SDHB Ile127Ser exhibits enzymatic activity and mitochondrial SDH assembly similar to wild-type (Kim 2015), elevated levels of succinate or loss of SDHB on immunohistochemistry were identified in the tumors of individuals with this variant suggesting an alternate method of pathogenicity (Pollard 2005, Kim 2017). SDHB Ile127Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the 2Fe-2S ferredoxin-type domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider SDHB Ile127Ser to be a pathogenic variant.
Invitae RCV000464351 SCV000553991 pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 127 of the SDHB protein (p.Ile127Ser). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with paraganglioma, metastatic paraganglioma, pheochromocytoma, and gastrointestinal stromal tumor (PMID: 15987702, 19802898, 21820839, 16912137, 19001511, 16317055, 23282968, 17200167, 19215943, 25683602). It was also shown to segregate with disease in a single family (PMID: 16916404). ClinVar contains an entry for this variant (Variation ID: 183814). An experimental study has shown that this missense change has no clear effect on either mitochondrial succinate dehydrogenase (SDH) assembly, SDH activity, or the interaction with SDH subunit A (SDHA) in vitro (PMID: 25972245). In summary, this variant is a rare missense change that has been reported in many affected individuals, and segregates with disease in a single family. Although experimental evidence suggests that this change preserves protein function, the clinical significance of these findings is uncertain and is outweighed by the genetic data from numerous clinical reports. Therefore, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc RCV000660256 SCV000782275 pathogenic Paragangliomas 4 2016-11-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000505708 SCV000843760 likely pathogenic not provided 2018-05-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000505708 SCV000886093 likely pathogenic not provided 2018-06-10 criteria provided, single submitter clinical testing The SDHB c.380T>G; p.Ile127Ser variant (rs786201095) has been observed in multiple individuals with a personal history of pheochromocytoma, paraganglioma, and/or gastrointestinal stromal tumor (Benn 2006, Bolland 2006, Brouwers 2006, Collins 2012, Miettinen 2013). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 183814) and observed in the European (Non-Finnish) population at a low overall frequency of 0.0027% (3/111678 alleles) in the Genome Aggregation Database. The isoleucine at codon 127 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Functional studies demonstrate that this variant exhibits enzymatic activity and mitochondrial SDH assembly similar to wild-type (Kim 2015), however levels of succinate were elevated in the tumors of individuals with this variant (Pollard 2005). Based on available information, this variant is considered likely pathogenic. References: Benn D et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Bolland M et al. Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma. ANZ J Surg. 2006 Aug;76(8):763-4. Brouwers F et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. Collins N et al. Contiguous bilateral head and neck paragangliomas in a carrier of the SDHB germline mutation. J Vasc Surg. 2012 Jan;55(1):216-9. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. Miettinen M et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013 Feb;37(2):234-40. Pollard P et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005 Aug 1;14(15):2231-9.
Integrated Genetics/Laboratory Corporation of America RCV000780706 SCV000918201 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The SDHB c.380T>G (p.Ile127Ser) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was absent in ExAC but was found in 3/246418 control chromosomes. This variant has been reported in multiple affected families/patients with variable phenotype including paragangliomas and GIST with evidence of co-segregation of the variant with disease (Pollad_2005, Benn_2006, Brouwers_2006, Joshua_2009, Thrimmers_2007 and Bolland_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Functional studies show activity comparable to WT level (Kim_SDHB_ERC_2015). This functional evidence is outweighted by strong clinical data which support a causative role of this variant. Taken together, this variant is classified as likely pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826205 SCV000967763 pathogenic Gastrointestinal stroma tumor; Hereditary Paraganglioma-Pheochromocytoma Syndromes 2018-07-13 criteria provided, single submitter clinical testing The p.Ile127Ser variant in SDHB has been reported in over 40 individuals with pa ragangliomas, pheochromocytomas, or gastrointestinal stromal tumors (GISTs) and segregated with disease in at least 7 relatives in these families (Bolland 2006, Benn 2006, Timmers 2007, Miettinen 2013, Martucci 2015, Sue 2015, Boikos 2016, Jochmanova 2017, Andrews 2018). This variant has also been reported in ClinVar ( Variation ID# 183814). In addition, three other variants at this position (p.Ile 127Asn, p.Ile127Leu, p.Ile127Thr) have been reported in the HGMD database in ind ividuals with paraganglioma, pheochromocytoma, and renal cell carcinoma (Stenson 2017). In vitro functional studies provide some evidence that the p.Ile127Ser v ariant may not impact protein function (Kim 2015). However, these types of assay s may not accurately represent biological function. This variant has been identi fied in 3/111678 European chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conserva tion analysis suggest that the p.Ile127Ser variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, this variant meets criteria to be classified as pathogenic for hereditary pa raganglioma/pheochromocytoma and GIST in an autosomal dominant manner based upon its presence in affected individuals, segregation studies, and low frequency in controls. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3.
Section on Endocrinology and Genetics,National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development RCV000170330 SCV000222639 likely pathogenic Carney triad no assertion criteria provided clinical testing

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