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 The p.V140F pathogenic mutation (also known as c.418G>T), located in coding exon 4 of the SDHB gene, results from a G to T substitution at nucleotide position 418. The valine at codon 140 is replaced by phenylalanine, an amino acid with highly similar properties. In one study, this mutation was detected in a 13-year-old boy diagnosed with an abdominal paraganglioma whose mother (also a carrier) was diagnosed with a thoracic paraganglioma at the age of 14 (Santiago AH et al. J. Pediatr. Endocrinol. Metab., 2010 Apr;23:419-22). In another study, two siblings were found to be carriers of this alteration, a 55-year-old woman and her 49-year-old brother, both of whom were diagnosed with a paraspinal paraganglioma. Their mother, however, was 76 years old and unaffected with cancer, suggesting reduced penetrance. Of note, this family also had a deceased sibling who was diagnosed with a neuroblastoma as an infant, metastatic extra adrenal sympathetic paragangliomas reminiscent of pheochromocytomas as a young adult, and renal cell carcinoma as an adult. It is not known whether this sibling was a carrier of this alteration (Schimke RN et al. Am. J. Med. Genet. A, 2010 Jun;152A:1531-5). A retrospective study looking at genotype-phenotype correlations of SDHB mutation carriers identified 4 patients with this variant; however, only one of these patients had PGL/PCC, again suggesting reduced penetrance (Rijken JA et al. Clin. Genet. 2018 Jan;93(1):60-66). In a recent study, 16 family members of 9 index patients with this mutation were found to carry it; however, only 5 of these family members were found to have disease when they underwent screening for PGL/PCC. This study suggests that the penetrance of p.V140P is 50% at age 38 (Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435). This variant has also been reported in other cases of childhood metastatic paragangliomas where the carrier parent has been unaffected, again suggesting possible decreased penetrance (Prodanov T et al. Pediatr. Nephrol., 2009 Jun;24:1239-42; Majumdar S et al. Pediatr Blood Cancer, 2010 Mar;54:473-5). In addition, this mutation was detected in an individual with pheochromocytoma whose tumor demonstrated absent SDHB staining on immunohistochemistry (van Nederveen FH et al. Lancet Oncol., 2009 Aug;10:764-71). This alteration has also been identified in 2/27 patients with urinary bladder paraganglioma (Martucci VL et al. Urol. Oncol., 2015 Apr;33:167.e13-20). Based on internal structural analysis, this mutation is anticipated to result in a significant decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 2020-10-25 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.