ClinVar Genomic variation as it relates to human health

Observed frequently in unrelated patients from different ethnic backgrounds with SDHB-related tumors, several of whom had tumor studies consistent with pathogenic variants in this gene (PMID: 18840642, 19189136, 19576851, 19927285, 20503330, 22588707, 25683602, 29204718, 30050099); Segregates with disease in many affected individuals in several kindreds referred for genetic testing at GeneDx and in published literature (PMID: 20583550, 20503330); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26236513, 20418362, 22588707, 29386252, 34906457, 30050099, 16912137, 20503330, 19927285, 20583550, 19189136, 18840642, 19576851, 22270996, 19802898, 25025441, 25683602, 26273102, 27910947, 27171833, 28374168, 28490599, 28748451, 29204718, 28503760, 29951630, 28152038, 32062700, 32035780, 32741965, 30787465, Hochfelder[abstract], 34703596, 20213850, 34308104, 27535533)

Variant summary: SDHB c.418G>T (p.Val140Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251978 control chromosomes. c.418G>T has been reported in the literature in multiple individuals affected with features of Hereditary Paraganglioma-Pheochromocytoma Syndrome and a reduced penetrance in some families (examples, Brouwers_2006, Meyer-Rochow_2008, Trimmers_2007, Santiago_2010, Lodish_2010, Ricketts_2010, Majumdar_2010, Muth_2012, Prodanov_2009, Schimke_2010, Bayley_2010). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function has been ascertained. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:20503330, 20583550, 30050099, 16912137, 19576851]. This variant is expected to disrupt protein structure [Myriad internal data].

This missense variant replaces valine with phenylalanine at codon 140 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty individuals affected with hereditary paragangliomas/pheochromocytomas, including children (PMID: 16912137, 18840642, 19189136, 19215943, 19927285, 20418362, 20503330, 20583550, 25683602, 26236513, 27171833, 28503760, 29951630, 20503330). This variant has been shown to segregate with disease in two unrelated families (PMID: 20503330, 20583550). Multiple carrier individuals from one of these families were unaffected with SDHB-associated disease. One study has reported detection of this variant in 16 family members of 9 index patients, however, only 5 of these 16 family members were found to have paragangliomas/pheochromocytomas (PMID: 28374168). This study suggested that the penetrance of this variant is 50% at age 38. This variant has been identified in 3/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 140 of the SDHB protein (p.Val140Phe). This variant is present in population databases (rs267607032, gnomAD 0.003%). This missense change has been observed in individuals with paraganglioma (PGL) and malignant PGL (PMID: 16912137, 19189136, 19802898, 19927285, 20503330, 20583550, 26236513). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18454). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces valine with phenylalanine at codon 140 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty individuals affected with hereditary paragangliomas/pheochromocytomas, including children (PMID: 16912137, 18840642, 19189136, 19215943, 19927285, 20418362, 20503330, 20583550, 25683602, 26236513, 27171833, 28503760, 29951630, 20503330). This variant has been shown to segregate with disease in two unrelated families (PMID: 20503330, 20583550). Multiple carrier individuals from one of these families were unaffected with SDHB-associated disease. One study has reported detection of this variant in 16 family members of 9 index patients, however, only 5 of these 16 family members were found to have paragangliomas/pheochromocytomas (PMID: 28374168). This study suggested that the penetrance of this variant is 50% at age 38. This variant has been identified in 3/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

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.

The SDHB c.418G>T variant is predicted to result in the amino acid substitution p.Val140Phe. This variant was reported in multiple patients with paraganglioma (Brouwers et al. 2006. PubMed ID: 16912137; Niemeijer et al. 2017. PubMed ID: 28490599; Andrews et al. 2018. PubMed ID: 29386252; Rijken et al. 2018. PubMed ID: 29951630; Richter et al. 2018. PubMed ID: 30050099). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/18454/). This variant is interpreted as pathogenic.

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.