ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.219+5G>C

dbSNP: rs1554812252
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519277 SCV000617305 pathogenic not provided 2015-12-02 criteria provided, single submitter clinical testing The c.219+5 G>C pathogenic variant has been reported previously in one individual with HHT, and was absent in 288 control alleles (Lesca et al., 2006). Furthermore, the c.219+5 G>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant destroys the canonical splice donor site in intron 2 and functional studies show that it causes skipping of exon 2 (Lesca et al., 2006). Other splice site variants in the ENG gene have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014).In summary, c.219+5 G>C in the ENG gene is interpreted as a pathogenic variant.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV002225644 SCV002503906 likely pathogenic See cases 2021-12-07 criteria provided, single submitter clinical testing The c.219+5G>T variant has not been reported in the medical literature and is absent from the general population (gnomAD v2.1.1). However, variants at the same position (c.219+5G>A and c.219+5G>C) have been reported in the literature in association with HHT (PMID: 12673790, PMID: 16705692). Cymerman et al (PMID: 12673790) showed evidence of exon skipping in two infants (family #130 in the study) with the c.219+5G>A variant, both of whom were asymptomatic for HHT at that time but had a positive family history. (PMID: 12673790). Lesca et al (PMID: 16705692) describe an individual (patient 25574 in Table 2) with a clinical diagnosis of HHT who was found to have the c.219+5G>C variant, which led to skipping of exon 2. This variant was found to be de novo.

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