ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.424-1G>A (rs1131691060)

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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 RCV000492109 SCV000581211 pathogenic Hereditary cancer-predisposing syndrome 2015-12-21 criteria provided, single submitter clinical testing The c.424-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 5 of the SDHB gene. This mutation (designated asIVS4-1G>A) has been detected in a youngmale diagnosed withextra-adrenal PGL at age 15 and a positive family history of disease(BennDE et al,Oncogene2003 Mar; 22(9):1358-64).This nucleotide position is highly conserved in available vertebrate species. In addition,theBDGP and ESEfinder in silico splicing modelspredictthat this alteration will abolish the native splice acceptor site; however experimental evidence is not currently available.In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice acceptor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med.2008;10:294).
Invitae RCV001244653 SCV001417887 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-10-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the SDHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with paraganglioma-pheochromocytoma syndrome (PMID: 12618761). ClinVar contains an entry for this variant (Variation ID: 428931). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). 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.

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