ClinVar Genomic variation as it relates to human health

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.

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.

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.

Published functional studies are inconclusive: enzymatic activity and mitochondrial SDH assembly similar to wild-type; elevated levels of succinate or loss of SDHB on immunohistochemistry suggesting an alternate method of pathogenicity (PMID: 25972245, 28070496, 15987702); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26916530, 19215943, 25394176, 15987702, 17667967, 24886695, 25972245, 21820839, 16912137, 19802898, 17200167, 25014000, 25683602, 16317055, 16916404, 25371406, 19001511, 28070496, 28738844, 28374168, 29386252, 28973655, 23083876, 28152038, 30728895, 30303539, 23282968, 30050099, 31447099, 30787465, 32741965, 33087929, 34906457, 32782288, 34308366, 35668420)

This missense variant replaces isoleucine with serine at codon 127 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). Functional studies do not support pathogenicity, but may not be measuring the deficiency associated with this ferredoxin domain variant (PMID: 15987702, 25972245, 28070496, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma in the literature (PMID: 15987702, 16317055, 16912137,16916404,17200167, 17667967,19001511,19802898, 21820839, 23282968, 25371406, 25683602, 28374168, 29386252). The variant has also been observed to segregate or occur in a familial context in several of these families (PMID: 16916404, 16317055, 25683602, 28374168, 29386252). This variant has been identified in 3/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

The p.I127S pathogenic mutation (also known as c.380T>G), located in coding exon 4 of the SDHB gene, results from a T to G substitution at nucleotide position 380. The isoleucine at codon 127 is replaced by serine, an amino acid with dissimilar properties. This mutation is located in the iron-sulphur cluster binding domain of SDHB. One study detected this mutation in the germline of an individual with a history of paraganglioma. DNA analysis of the paraganglioma tumor identified a deletion of 1p encompassing the SDHB locus (Pollard PJ et al. Hum. Mol. Genet. 2005 Aug;14:2231-9). This alteration has been reported in numerous individuals with paraganglioma, pheochromocytoma, and/or gastrointestinal stromal tumor (GIST) (Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov;91:4505-9; Collins N and Dietzek A J. Vasc. Surg. 2012 Jan;55:216-9; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). 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.

This missense variant replaces isoleucine with serine at codon 127 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). Functional studies do not support pathogenicity, but may not be measuring the deficiency associated with this ferredoxin domain variant (PMID: 15987702, 25972245, 28070496, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma in the literature (PMID: 15987702, 16317055, 16912137,16916404,17200167, 17667967,19001511,19802898, 21820839, 23282968, 25371406, 25683602, 28374168, 29386252). The variant has also been observed to segregate or occur in a familial context in several of these families (PMID: 16916404, 16317055, 25683602, 28374168, 29386252). This variant has been identified in 3/251458 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 isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 127 of the SDHB protein (p.Ile127Ser). This variant is present in population databases (rs786201095, gnomAD 0.003%). This missense change has been observed in individuals with paraganglioma, metastatic paraganglioma, pheochromocytoma, and gastrointestinal stromal tumor (PMID: 15987702, 16317055, 16912137, 16916404, 17200167, 19001511, 19215943, 19802898, 21820839, 23282968, 25683602). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183814). 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%. Experimental studies have shown that this missense change does not substantially affect SDHB function (PMID: 25972245). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been 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: 16916404, 30050099, 24623741, 31308404, 29386252, 30201732]. This variant is expected to disrupt protein structure [Myriad internal data].