ClinVar Miner

Submissions for variant NM_003001.3(SDHC):c.405+1G>T (rs587776653)

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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 RCV000574152 SCV000675103 pathogenic Hereditary cancer-predisposing syndrome 2016-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Gharavi Laboratory,Columbia University RCV000681938 SCV000809424 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Invitae RCV000641917 SCV000763567 likely pathogenic Gastrointestinal stroma tumor; Paragangliomas 3 2018-01-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 5) of the SDHC gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs587776653, ExAC 0.001%). This variant has been reported in an individual affected with metastatic paraganglioma at the carotid bifurcation (PMID: 12658451), and in an individual with sporadic paraganglioma (PMID: 22517554). ClinVar contains an entry for this variant (Variation ID: 7242). Different variants at this nucleotide (c.405+1G>A, c.405+1G>C) have been reported in individuals affected with paraganglioma and gastrointestinal stromal tumors (GIST) (PMID: 17667967, 24402737, 24758179). Experimental studies have shown that this intronic change alters RNA splicing, and results in skipping of exon 5 and a truncated protein product lacking C-terminal amino acid sequence (PMID: 12658451). While experimental studies elucidating the function of the truncated protein have not been published, a deletion of exon 6 has been determined to be pathogenic (PMID: 15342702). This suggests that disruption of the C-terminal region of the SDHC protein is causative of disease. 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.
OMIM RCV000007664 SCV000027865 pathogenic Paragangliomas 3 2000-11-01 no assertion criteria provided literature only

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