ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.360+5G>C (rs1060501417)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477368 SCV000546123 likely pathogenic Hereditary hemorrhagic telangiectasia type 1 2017-11-06 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein, but it affects a nucleotide within the consensus splice site of the intron. This variant has been reported in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 17384219, Invitae Database). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000485643 SCV000573684 likely pathogenic not provided 2017-03-10 criteria provided, single submitter clinical testing A c.360+5 G>C variant that is likely pathogenic was identified in the ENG gene. The c.360+5 G>C variant has been previously reported in one individual with a confirmed clinical diagnosis of HHT (Gedge et al., 2007); although, further clinical details and segregation studies were not reported. The c.360+5 G>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico splice prediction programs predict this variant destroys the natural splice donor site in intron 3 which is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the ENG gene have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, this substitution occurs at a nucleotide that is conserved in mammals. Finally, a likely pathogenic variant at the same nucleotide position (c.360+5 G>A) has also been reported in association with HHT (Letteboer et al., 2005), supporting the functional significance of this nucleotide.

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