ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.418G>T (p.Val140Phe) (rs267607032)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132167 SCV000187244 pathogenic Hereditary cancer-predisposing syndrome 2019-06-11 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;Significant disease association in appropriately sized case-control study(ies);Structural Evidence
GeneDx RCV000505751 SCV000235632 pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHB c.418G>T at the cDNA level, p.Val140Phe (V140F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant has been observed in multiple individuals with malignant and/or multifocal paragangliomas, pheochromocytomas, and/or renal cell carcinoma, with at least one tumor demonstrating loss of SDHB protein expression on immunohistochemistry (Timmers 2008, Prodanov 2009, van Nederveen 2009, Majumdar 2010, Schimke 2010, Porzig 2012, Martucci 2015, Jha 2017). Additionally, segregation studies have found this variant to segregate with disease in at least two kindreds (Schimke 2010, Santiago 2010). SDHB Val140Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). SDHB Val140Phe is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider SDHB Val140Phe to be pathogenic.
Invitae RCV000627753 SCV000287774 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 140 of the SDHB protein (p.Val140Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with paraganglioma (PGL) and malignant PGL (PMID: 16912137, 19189136, 19927285, 19802898, 26236513), with evidence of segregation with SDHB-associated disease in two families (PMID: 20583550, 20503330). ClinVar contains an entry for this variant (Variation ID: 18454). Structural prediction analysis based on the crystal structure of porcine mitochondrial complex II predicts that this variant may affect key structural residues (PMID: 19802898). In addition, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. However, these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000013634 SCV000488516 likely pathogenic Paragangliomas 4 2016-04-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000013634 SCV000596999 likely pathogenic Paragangliomas 4 2015-12-07 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000505751 SCV000843761 likely pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing
OMIM RCV000013634 SCV000033881 pathogenic Paragangliomas 4 2010-06-01 no assertion criteria provided literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505378 SCV000599477 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research The penetrance of the disease in SDHB mutations carriers is not 100%, it is about 45-50%. There apparently are other factors contributing to disease development, however those are yet not known.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.