ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1432_1432+1del (rs878854627)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228421 SCV000288110 likely pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2020-08-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the SDHA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with head and neck paraganglioma and melanoma (PMID: 29177515, 26556299, 30877234). ClinVar contains an entry for this variant (Variation ID: 239647). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000567345 SCV000664480 pathogenic Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing The c.1432_1432+1delGG pathogenic mutation spans the coding exon 10/intron 10 boundary of the SDHA gene and results from the deletion of 2 nucleotides at nucleotide positions c.1432 and c.1432+1. The deleted region includes the canonical donor site, which is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001253762 SCV001429631 pathogenic Pheochromocytoma; Paraganglioma 2020-07-10 criteria provided, single submitter clinical testing This variant has been observed in a male proband with phaeochromocytoma and lung nodule. The variant has previously been reported in the literature, including in a male with glomus jugulare tumour (PMID: 29177515); a male with retroperitoneal paraganglioma (PMID 28384794); a male with gallbladder paraganglioma, pancreatic neuroendocrine tumour and metastatic prostate cancer (PMID: 32534711); and a female with thoracic paraganglioma (PMCID: PMC7209502) (PS4_moderate). The variant is absent from population database gnomAD (PM2_supporting) and is predicted to result in loss of protein function (PVS1_very_strong). Data included in classification: Prevalence in affected versus controls GT-AG 1,2 splice site variant predicted to result in loss of protein function Data not included in classification: Functional data

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