ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.360+4A>G

dbSNP: rs1564457752
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV000018151 SCV001441155 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2018-01-01 criteria provided, single submitter research PS3+PM2+PP4
Labcorp Genetics (formerly Invitae), Labcorp RCV001851903 SCV002277734 likely pathogenic Hereditary hemorrhagic telangiectasia 2021-09-24 criteria provided, single submitter clinical testing Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 9245986). 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. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 9245986, 32573726). ClinVar contains an entry for this variant (Variation ID: 16671). 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.
Ambry Genetics RCV004018638 SCV005037529 likely pathogenic Cardiovascular phenotype 2017-02-20 criteria provided, single submitter clinical testing The c.360+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 3 in the ENG gene. This variant was identified in an individual with hereditary hemorrhagic telangiectasia (HHT) and was reported to result in a donor splice site disruption; mRNA analysis showed exon 3 skipping (Shovlin CL et al. Am. J. Hum. Genet., 1997 Jul;61:68-79). In our internal cohort, this variant was identified in an individual with telangiectasias, epistaxis, and arteriovenous malformations. This variant was not reported in the ExAC database, with coverage at this position. This nucleotide position is highly conserved on limited sequence alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV004700247 SCV005201597 likely pathogenic not provided 2023-11-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); A published functional study showed a splice defect resulting in a truncated protein (PMID: 9245986); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 32573726, 9245986)
OMIM RCV000018151 SCV000038430 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 1997-07-01 no assertion criteria provided literature only

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