ClinVar Genomic variation as it relates to human health

The SDHC c.43C>T; p.Arg15Ter variant (rs201286421) is reported in the literature in multiple individuals affected with paraganglioma, gastrointestinal stromal tumors, or adrenocortical cancer (Else 2017, Illouz 2012, Pasini 2008, Renella 2014, Vandy 2011). This variant is found on only two chromosomes in the Genome Aggregation Database (2/248902 alleles), indicating it is not a common polymorphism. 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: Else T et al. Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series. Eur J Endocrinol. 2017;177(5):439-444. Illouz F et al. Long-delayed localization of a cardiac functional paraganglioma with SDHC mutation. Ann Intern Med. 2012;157(3):222-223. Pasini B et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008;16(1):79-88. Renella R et al. Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies. Fam Cancer. 2014;13(3):507-511. Vandy FC et al. Synchronous carotid body and thoracic paraganglioma associated with a germline SDHC mutation. J Vasc Surg. 2011;53(3):805-807.

Variant summary: SDHC c.43C>T (p.Arg15X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Paraganglioma-Pheochromocytoma in HGMD . The variant allele was found at a frequency of 8e-06 in 248902 control chromosomes (gnomAD). c.43C>T has been reported in the literature in multiple individuals affected with Paraganglioma-Pheochromocytoma (example: Williams_2021). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant changes 1 nucleotide in exon 2 of the SDHC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with phaeochromocytoma/paraganglioma (PMID: 19351833, 19454582, 21106325, 22868853, 24758179, 24781345, 28412079, 34558728). This variant has been identified in 2/248902 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.

The p.Arg15X variant in SDHC has been reported in at least 6 individuals with SDHC-associated cancers (Pasini 2008, Vandy 2011, Illouz 2012, Renella 2014, Else 2014). This variant has been identified in 0.003% (1/30594) South Asian chromosomes by chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 15, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SDHC gene is an established disease mechanism in individuals with hereditary paragangliomas and pheochromocytomas. In summary, this variant meets criteria to be classified as pathogenic for hereditary paragangliomas and pheochromocytomas in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19351833, 24781345, 24758179, 22517557, 27600092, 25525159, 19454582, 22703879, 22868853, 23934599, 17898811, 26269449, 26046366, 28412079, 28594934, 21106325, 29878124, 30050099, 28819017, 30301441, 27279923, 17667967, 32561571, 32741965, 30787465, 35668420, 34558728, 35731023, 33087929)

This sequence change creates a premature translational stop signal (p.Arg15*) in the SDHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHC are known to be pathogenic (PMID: 17667967, 19454582, 23282968, 24758179). This variant is present in population databases (rs201286421, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with paraganglioma, Hodgkin's lymphoma, pheochromocytoma, and/or gastrointestinal stromal tumors (PMID: 17667967, 19351833, 21106325, 22868853, 24781345). ClinVar contains an entry for this variant (Variation ID: 41776). For these reasons, this variant has been classified as Pathogenic.

The c.43C>T (p.Arg15*) variant of the SDHC gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumors, and adrenocortical cancer (PMID: 17667967, 19351833, 21106325, 22868853, 24758179, 24781345, 27279923, 28412079). This variant has been identified in 2/248902 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss-of-function variants in SDHC are known to be pathogenic (PMID: 19546167, 17667967). Therefore, the c.43C>T (p.Arg15*) variant of the SDHC gene is classified as pathogenic.

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

The p.R15* pathogenic mutation (also known as c.43C>T), located in coding exon 2 of the SDHC gene, results from a C to T substitution at nucleotide position 43. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been observed in multiple individuals/families with various types of paraganglioma (PGL) (Pasini B et al. Eur J Hum Genet, 2008 Jan;16:79-88; Vandy FC et al. J. Vasc. Surg., 2011 Mar;53:805-7; llouz F et al. Ann. Intern. Med., 2012 Aug;157:222-3; Renella R et al. Fam. Cancer, 2014 Sep;13:507-11; Else T et al. J Clin Endocrinol Metab, 2014 Aug;99:E1482-6; Bennedbæk M et al. Hered Cancer Clin Pract, 2016 Jun;14:13; L'Huillier V et al. Eur Ann Otorhinolaryngol Head Neck Dis, 2017 Apr; Neumann HP et al. Cancer Res, 2009 Apr;69:3650-6; Smith JD et al. OTO Open Mar;5:2473974X21995453; Richter S et al. Genet Med, 2019 03;21:705-717; McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Ong RKS et al. J Clin Endocrinol Metab, 2018 08;103:2802-2806). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Converted during submission to Pathogenic.

The SDHC c.43C>T variant is predicted to result in premature protein termination (p.Arg15*). This variant has been reported in multiple individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumors, and adrenocortical cancer (Pasini et al. 2008. PubMed ID: 17667967; Vandy et al. 2010. PubMed ID: 21106325; Illouz et al. 2012. PubMed ID: 22868853; Renella et al. 2014. PubMed ID: 24781345; Else et al. 2017. PubMed ID: 28819017). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41776/). Nonsense variants in SDHC are expected to be pathogenic. This variant is interpreted as pathogenic.