Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000231881 | SCV000288140 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-09-03 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 4 of the SDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 239672). This variant is also known as c.457-3_457-1delCAG. Disruption of this splice site has been observed in individuals with gastrointestinal stromal tumor (GIST) (PMID: 23109135, 23612575; Invitae). This variant is not present in population databases (gnomAD no frequency). |
| “Giorgio Prodi” Cancer Research Center, |
RCV001799643 | SCV002026138 | pathogenic | Gastrointestinal stromal tumor | 2021-10-01 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV002338730 | SCV002637427 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-06-18 | criteria provided, single submitter | clinical testing | The c.457-2_457delAGC pathogenic mutation results from a deletion of AGC nucleotides between positions 457-2 and 457 and involves the canonical splice acceptor site before coding exon 5 of the SDHA gene. This mutation (also designated as c.457-3_457-1delCAG) has been reported as germline in individuals with gastrointestinal stromal tumors (GISTs) that demonstrated absent SDHB staining by IHC (Belinsky MG et al. Genes Chromosomes Cancer 2013 02;52(2):214-24; Pantaleo MA et al. Eur J Hum Genet 2014 Jan;22(1):32-9). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor 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). In addition to the clinical data presented in the literature, 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 interpreted as a disease-causing mutation. |