Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000492714 | SCV000581219 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-12-18 | 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 variant was reported in individual(s) with features consistent with paraganglioma-pheochromocytoma syndrome (Else T et al. J Clin Endocrinol Metab, 2014 Aug;99:E1482-6). Other variant(s) impacting the same donor site (c.405+1G>T) have been identified in individual(s) with features consistent with paraganglioma-pheochromocytoma syndrome (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). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that c.405+1G>C 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
Labcorp Genetics |
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, |
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]. |