ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.77+2dup

dbSNP: rs766486676
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001038332 SCV001201798 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 3 2021-05-21 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with head and neck paraganglioma (PMID: 23666964). This variant is present in population databases (rs766486676, ExAC 0.002%). This sequence change falls in intron 2 of the SDHC gene. It does not directly change the encoded amino acid sequence of the SDHC protein, but it affects a nucleotide within the consensus splice site of the intron.
Ambry Genetics RCV002400228 SCV002670524 pathogenic Hereditary cancer-predisposing syndrome 2020-11-16 criteria provided, single submitter clinical testing The c.77+2dupT intronic pathogenic mutation, results from a duplication of one nucleotide at position c.77+2 after intron 2 of the SDHC gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration has been reported in multiple individuals with a personal history consistent with hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC) (Buffet A et al. Horm Metab Res, 2012 May;44:359-66; Rattenberry E et al. J Clin Endocrinol Metab, 2013 Jul;98:E1248-56). Further, two other alterations impacting this canonical donor site (c.77+1G>A, c.77+1G>C) have been reported in individuals with a personal history consistent with hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC) (Ambry internal data). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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