ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.129G>A (p.Trp43Ter) (rs104894308)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222413 SCV000276168 pathogenic Hereditary cancer-predisposing syndrome 2018-11-06 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000627761 SCV000645368 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2017-09-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp43*) in the SDHD gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with paraganglioma in a single family (PMID: 18211978) and also has been observed in unrelated individuals with paraganglioma (PMID: 12111639, 19454582, 18561749, 20098451) and gastrointestinal stromal tumor (PMID: 20098451). This variant has been described as a likely common cause of disease in the Spanish population (PMID: 19258401). ClinVar contains an entry for this variant (Variation ID: 6913). Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756632 SCV000884504 pathogenic not provided 2017-08-11 criteria provided, single submitter clinical testing The SDHD c.129G>A, p.Trp43Ter variant (rs104894308) has been reported in multiple families with head and neck paraganglioma (Benn 2008, Cascon 2002, Timmers 2008), and segregating with affected individuals (Pigny 2008, Valesco 2005). It is listed as pathogenic in ClinVar (Variation ID: 6913), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Benn D et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006; 91(3):827-36. Cascon A et al. Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. Eur J Hum Genet. 2002; 10(8):457-61. Pigny P et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab. 2008; 93(5):1609-15. Timmers H et al. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. Clin Endocrinol (Oxf). 2008; 68(4):561-6. Velasco A et al. Mutation analysis of the SDHD gene in four kindreds with familial paraganglioma: description of one novel germline mutation. Diagn Mol Pathol. 2005; 14(2):109-14.
OMIM RCV000007322 SCV000027520 pathogenic Paragangliomas 1 2008-05-01 no assertion criteria provided literature only

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