ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1664-2A>G

dbSNP: rs2126633124
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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 RCV001379935 SCV001577836 likely pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2020-09-23 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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. Donor and acceptor splice site variants 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). 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 not been reported in the literature in individuals with SDHA-related conditions. This sequence change affects an acceptor splice site in intron 12 of the SDHA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics RCV002404895 SCV002706571 likely pathogenic Hereditary cancer-predisposing syndrome 2021-08-27 criteria provided, single submitter clinical testing The c.1664-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 13 in the SDHA gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. 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 classified as likely pathogenic.

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