ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys) (rs104894304)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155750 SCV000205461 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2013-05-20 criteria provided, single submitter clinical testing The Tyr114Cys variant in SDHD was originally reported in one German individual w ith familial paraganglioma (Milunsky, 2001) and subsequently reported in one Aus trian individual with hereditary neck paraganglioma (HNPGL) where the variant se gregated with disease in 7 affected relatives from the same family (Fish, 2007). Recently, the Tyr114Cys variant has been reported to have arisen as a founder effect in a population originating from the region surrounding Torentino, Italy (Schiavi, 2012). Schiavi and colleagues studied 15 Italian index cases with HNPG L and found the Tyr114Cys variant segregated with disease in 138 affected relati ves from 95 families (Schiavi, 2012). Functional studies have shown that the Tyr 114Cys variant impacts protein function, and results in complete loss of ubiquin one reductase activity in yeast (Panizza, 2013). However, this in vitro assay ma y not accurately represent biological function. This variant has not been identi fied in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Tyr1 14Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria t o be classified as pathogenic ( based upon segrega tion studies, absence from controls and functional evidence supporting the varia nt causing a functional defect on the protein.
Ambry Genetics RCV000221353 SCV000275206 pathogenic Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing The p.Y114C pathogenic mutation (also known as c.341A>G), located in exon 4 of the SDHD gene, results from an A to G substitution at nucleotide position 341. The tyrosine at codon 114 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been identified in multiple individuals affected with paragangliomas (PGL) and/or pheochromocytomas (Neumann H et al. JAMA. 2004 Aug 25;292(8):943-51; Liapis C et al. Anticancer Res. 2005 May-Jun;25(3c):2449-52; Benn D et al. J. Clin. Endocrinol. Metab. 2006 Mar;91(3):827-36; Antonello M et al. Eur. J. Vasc. Endovasc. Surg. 2008 Nov;36(5):517-9; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr 10;19(2):149-55; Zdrojowy-WeÅ‚na A and Bednarek-Tupikowska G. Neuro Endocrinol. Lett. 2014;35(5):355-8; Bennedbæk M et al. Hered. Cancer Clin. Pract. 2016 Jun;14:13). In addition, this mutation showed strong segregation with disease among 38 screened members of a family affected with head and neck PGL (Fish J et al. Head Neck. 2007 Sep;29(9):864-73). Another study indicated that the p.Y114C mutation in the SDHD gene is an Italian founder mutation after finding this alteration in 287 out of 540 individuals from 95 kindred who were diagnosed with head and neck PGL (Schiavi et al. J. Clin. Endocrinol. Metab. 2012 Apr;97(4):637-41). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000694891 SCV000823357 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 114 of the SDHD protein (p.Tyr114Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with pheochromocytomas and paragangliomas (PMID: 22456618, 11343322, 23433498, 27279923, 16317055, 29386252), and has been reported to segregate with disease in several families (PMID: 17563904, 16080474, 25275255). This variant is also described as a founder mutation of the Trentino area in Italy (PMID: 22456618). ClinVar contains an entry for this variant (Variation ID: 6900). Experimental studies have shown that this missense change causes severe functional defect with oxidative growth inability and increased mitochondrial DNA mutability in yeast complementation assay (PMID: 23175444). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289818 SCV001477811 pathogenic none provided 2019-07-26 criteria provided, single submitter clinical testing The SDHD c.341A>G; p.Tyr114Cys variant (rs104894304) is reported in the literature in multiple individuals and families affected with pheochromocytoma or paraganglioma (Andrews 2018, Antonello 2008, Benn 2006, Braun 2005, Fish 2007, Milunsky 2001, Neumann 2004, Piccini 2012, Richter 2019), and is a common variant in Italy due to a founder effect (Schiavi 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6900), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 114 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses in yeast demonstrate a complete loss of ubiquinone reductase activity (Panizza 2013). Based on available information, this variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Antonello M et al. Role of the genetic study in the management of carotid body tumor in paraganglioma syndrome. Eur J Vasc Endovasc Surg. 2008 Nov;36(5):517-9. Benn DE et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Braun S et al. Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas. Anticancer Res. 2005 Jul-Aug;25(4):2809-14. Fish JH et al. Systematic screening and treatment evaluation of hereditary neck paragangliomas. Head Neck. 2007 Sep;29(9):864-73. Milunsky JM et al. Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet. 2001 May 15;100(4):311-4. Neumann HP et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Panizza E et al. Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. Hum Mol Genet. 2013 Feb 15;22(4):804-15. Piccini V et al. Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55. Richter S et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019 Mar;21(3):705-717. Schiavi F et al. The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression. J Clin Endocrinol Metab. 2012 Apr;97(4):E637-41.
OMIM RCV000007309 SCV000027506 pathogenic Paragangliomas 1 2001-05-15 no assertion criteria provided literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000155750 SCV000599544 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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