ClinVar Miner

Submissions for variant NM_017841.2(SDHAF2):c.371-2A>G (rs375280597)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566130 SCV000675044 likely pathogenic Hereditary cancer-predisposing syndrome 2016-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000467864 SCV000552834 uncertain significance Hereditary Paraganglioma-Pheochromocytoma Syndromes 2018-03-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 3) of the SDHAF2 gene. While this 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 (rs375280597, ExAC 0.003%). This variant has not been reported in the literature in individuals with a SDHAF2-related disease. ClinVar contains an entry for this variant (Variation ID: 411604). Although donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in SDHAF2 are known to be pathogenic (PMID: 26096992, 22241717), the pathogenicity of this acceptor splice site variant in the last intron is inconclusive due to the uncertain impact on mRNA splicing and protein function. It has been classified as a Variant of Uncertain Significance.

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