ClinVar Miner

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

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Total submissions: 5
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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 Strong segregation with disease (lod >3 = >10 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000694891 SCV000823357 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 2019-10-21 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.
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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