ClinVar Miner

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

dbSNP: rs104894308
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Total submissions: 5
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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 2024-11-18 criteria provided, single submitter clinical testing The p.W43* pathogenic mutation (also known as c.129G>A) located in coding exon 2 of the SDHD gene, results from a G to A substitution at nucleotide position 129. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This variant has been identified in multiple individuals with a personal and/or family history of paragangliomas and/or pheochromocytomas (Cascon A et al. Eur. J. Hum. Genet. 2002 Aug; 10(8):457-61; Timmers HJ et al. Clin. Endocrinol. (Oxf). 2008 Apr;68:561-6). In addition to the clinical data presented in the literature, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002512871 SCV000645368 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2021-07-06 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). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). 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).
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.
Myriad Genetics, Inc. RCV000007322 SCV004019079 pathogenic Paragangliomas 1 2023-03-29 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
OMIM RCV000007322 SCV000027520 pathogenic Paragangliomas 1 2008-05-01 no assertion criteria provided literature only

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