ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.405+1G>C

dbSNP: rs587776653
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492714 SCV000581219 pathogenic Hereditary cancer-predisposing syndrome 2021-12-07 criteria provided, single submitter clinical testing The c.405+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the SDHC gene. This mutation has been detected in an individual with a head and neck paraganglioma (Else T et al. J Clin Endocrinol Metab, 2014 Aug;99:E1482-6). Another alteration impacting the same donor site (c.405+1G>T) has been described in multiple individuals with a paraganglioma (Niemann S et al. Hum Genet, 2003 Jul;113:92-4; Schiavi F et al. JAMA, 2005 Oct;294:2057-63; Lefebvre S et al. Horm Metab Res, 2012 May;44:334-8). c.405+1G>C is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000641918 SCV000763568 pathogenic Gastrointestinal stromal tumor; Paragangliomas 3 2023-09-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the SDHC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with paraganglioma and/or gastrointestinal stromal tumors (PMID: 12658451, 17667967, 17804857, 21173220, 24402737, 24758179, 26173966). ClinVar contains an entry for this variant (Variation ID: 428934). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a new termination codon (PMID: 12658451). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV004023285 SCV004930796 pathogenic Paragangliomas 3 2024-02-08 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24758179, 12658451, 26173966, 17667967].

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