ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1909-2A>G

gnomAD frequency: 0.00001  dbSNP: rs747939816
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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 RCV000565006 SCV000664451 likely pathogenic Hereditary cancer-predisposing syndrome 2023-12-08 criteria provided, single submitter clinical testing The c.1909-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 15 in the SDHA gene. This variant has been detected in individuals with pheochromocytoma and gastrointestinal stromal tumor (Casey RT et al. Mol Genet Genomic Med, 2017 May;5:237-250; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000692849 SCV000820694 likely pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2023-12-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 14 of the SDHA gene. While this variant 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 (rs747939816, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with gastrointestinal stromal tumor (PMID: 28546994; Invitae). ClinVar contains an entry for this variant (Variation ID: 480769). 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 is associated with inconclusive levels of altered splicing (Invitae). 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.
Myriad Genetics, Inc. RCV004024461 SCV004933669 likely pathogenic Paragangliomas 5 2024-02-08 criteria provided, single submitter clinical testing This variant is considered likely 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.

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