ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1311+5G>A

dbSNP: rs1830423993
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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 RCV001236499 SCV001409224 likely pathogenic Hereditary hemorrhagic telangiectasia 2023-04-22 criteria provided, single submitter clinical testing Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 962612). This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein. It affects a nucleotide within the consensus splice site.
Molecular Genetics, Royal Melbourne Hospital RCV002225129 SCV002503654 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2023-03-30 criteria provided, single submitter clinical testing This sequence change falls at position 5 in the splice region of the donor site of intron 10 of ENG. It is absent in a large population cohort (gnomAD v2.1 and v3.1). The variant has been identified in at least four unrelated probands with a confirmed clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT), and segregates with affected status over three families (Royal Melbourne Hospital; Edinburgh RGC; Pongpech S et al. J Med Assoc Thai 2018;101:1015-24; SCV001409224.2). Multiple lines of computational evidence predict an impact on splicing (SpliceAI, MaxEntScan, NNSplice), and multiple variants affecting this donor splice site have been reported as pathogenic in the HHT Mutation Database (https://arup.utah.edu/database/HHT). Based on the classification scheme RMH ACMG Guidelines v1.4.0, this variant is classified as a LIKELY PATHOGENIC. Following criteria are met: PS4, PP1_Moderate, PM2_Supporting, PP3.

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