ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

The p.R133* pathogenic mutation (also known as c.397C>T), located in coding exon 5 of the SDHC gene, results from a C to T substitution at nucleotide position 397. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration occurs at the 3' terminus of SDHC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 37 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function. This alteration has been reported in multiple unrelated individuals with paragangliomas (PGLs), gastrointestinal stromal tumors (GIST), renal cell carcinomas, and an adrenocortical carcinoma (Ricketts CJ et al. J. Urol., 2012 Dec;188:2063-71; Miettinen M et al, 2013 Feb;37:234-40; Bickmann JK et al. J. Clin. Endocrinol. Metab., 2014 Mar;99:E489-96; Else T et al. J Clin Endocrinol Metab, 2014 Aug;99:E1482-6; Lefebvre M et al. Curr Oncol, 2014 Feb;21:e8-e17; Else T et al. Eur J Endocrinol, 2017 Nov;177:439-444). In addition, this alteration has been identified in multiple individuals with PGLs of French Canadian descent (Bourdeau I et al. J Clin Endocrinol Metab, 2016 12;101:4710-4718). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The p.Arg133X variant in SDHC is believed to be a French Canadian founder variant and been reported in >20 individuals, of mainly French Canadian and French ancestry, with paragangliomas/pheochromocytomas (PGL/PCC: Zbuk 2007, Burnichon 2009, Ricketts 2012, Lefevre 2014, Bickmann 2014, Shuch 2016, Bourdeau 2016). This variant segregated with PGL/PCC in at least 4 affected relatives from 2 families (Bourdeau 2016). In another family (Shuch 2016), the p.Arg133X variant segregated with both renal cell carcinoma (2 affected relatives) and PGL/PCC (1 affected relative). The p.Arg133X variant has also been identified in 0.009% (3/30782) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org; dbSNP rs764575966). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 133. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~22% of the coding region, with 37 amino acids removed. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndromes in an autosomal dominant manner based on its presence in multiple affected individuals, segregation studies, and low frequency in controls. ACMG/AMP criteria applied: PVS1_Strong, PS4, PM2, PP1_Moderate.

The SDHC c.397C>T, p.Arg133Ter variant (rs764575966) has been reported in multiple patients diagnosed with hereditary paraganglioma syndrome (Bickmann 2014, Zbuk 2007), renal cancer (Ricketts 2012) or gastrointestinal tumors (Miettinen 2013). It is reported as pathogenic in ClinVar (Variation ID: 183753), and observed in the general population with an allele frequency of 0.004% (10/280,416 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Bickmann J et al. Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*). J Clin Endocrinol Metab. 2014; 99(3):E489-96. 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; 37(2):234-40. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012; 188(6):2063-71. Zbuk K et al. Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma. Nat Clin Pract Oncol. 2007; 4(10):608-12.

This sequence change results in the creation of a premature stop codon at amino acid position 133, p.Arg133*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SDHC protein with potentially abnormal function. This pathogenic sequence change has previously been described in several patient with paragangliomas (OMIM# 605373; Bickmann et. al., 2014; Lefebvre et. al., 2014; Zbuk et. al., 2007). This variant was also found in the germline heterozygous state in several family members that were affected with renal cell carcinoma (Ricketts et. al., 2012). Our interpretation is based on the current understanding of the genetics of SDHC-related disorders.

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22517557, 23282968, 26659639, 19351833, 28973655, 27634942, 24423348, 25525159, 17898811, 23083876, 19454582, 24523625, 24758179, 24102379, 25024072, 27493882, 27700540, 29339836, 26492543, 28819017, 29794110, 26490314, 29386252, 30201732, 31212687, 32272925, 33087929, 30787465, 31447099, 30877234)

This sequence change creates a premature translational stop signal (p.Arg133*) in the SDHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the SDHC protein. This variant is present in population databases (rs764575966, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with paragangliomas (PGLs) and gastrointestinal stromal tumor (PMID: 17898811, 23083876, 23282968, 24423348, 24523625, 24758179, 27700540). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183753). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 5 of the SDHC gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 24758179, 25024072, 27700540, 28819017), and over 10 individuals with sporadic paranganglioma (PMID: 34750850). This variant is described as a common variant in the French Canadian population (PMID: 27700540), and it has been observed that this variant segregates with disease (PMID: 25024072, 27700540, 28819017). This variant has been identified in 10/280416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

SDHC: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate