ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1311G>A (p.Arg437=)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001059848 SCV001224498 pathogenic Hereditary hemorrhagic telangiectasia 2019-12-03 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 observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 15517393). 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. A different variant affecting this nucleotide (c.1311G>C) has been determined to be pathogenic (PMID: 9554745, 21158752). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286216 SCV001472749 pathogenic Hereditary hemorrhagic telangiectasia type 1 2019-12-04 criteria provided, single submitter clinical testing The ENG c.1311G>A; p.Arg437Arg variant is reported in the literature in five individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Letteboer 2005). The five affected individuals with this variant were determined to share a common ancestor in the year 1745 (Letteboer 2005), suggesting the variant has segregated with disease over numerous meioses. The c.1311G>A variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is a synonymous variant in a moderately conserved nucleotide at the end of exon 10, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, although this has not yet been verified by RNA studies. Still, other variants at the same nucleotide (c.1311G>C, c.1311G>T) have been reported in individuals with HHT and are considered disease-causing (Gallione 1998, McDonald 2011), suggesting this position may be intolerant to sequence variation. Based on available information, the c.1311G>A variant is considered to be pathogenic. References: Gallione CJ et al. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286-94. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44.

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