ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1311G>T (p.Arg437=) (rs1554809448)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686208 SCV000813716 likely pathogenic Hereditary hemorrhagic telangiectasia 2018-12-07 criteria provided, single submitter clinical testing This sequence change affects codon 437 of the ENG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ENG protein. This variant also falls at the last nucleotide of exon 10 of the ENG coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 21158752, Invitae). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. Two additional variants affecting this nucleotide (c.1311G>C, c.1311G>A) has been determined to be pathogenic (PMID: 9554745, 15517393). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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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