ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.916_917delinsAA (p.Ala306Lys) (rs1060503244)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474312 SCV000552411 uncertain significance Hereditary hemorrhagic telangiectasia type 2 2016-11-18 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 7 of the ACVRL1 mRNA (c.916_917delGCinsAA), but otherwise preserves the integrity of the reading frame. This change replaces alanine with lysine at codon 306 of the ACVRL1 protein (p.Ala306Lys). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ACVRL1-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted/inserted nucleotides is currently unknown. In summary, this sequence change results in a missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000519342 SCV000618878 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACVRL1 gene. The c.916_917delGCinsAA variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.916_917delGCinsAA variant results in the deletion of two nucleotides and insertion of two nucleotides which does not cause a shift in reading frame and causes the amino acid substitution A306K. The A306K substitution is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and at a position where amino acids with similar properties to alanine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Two other missense variants in nearby residues (A306P, A306E) have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined.

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