ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.920C>A (p.Ala307Glu) (rs863223411)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200622 SCV000249630 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACVRL1 gene. The A307E variant has not been published as pathogenic or been reported as benign to our knowledge. The A307E variant is not observed in large population cohorts (Lek et al., 2016). The A307E variant 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. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV001238032 SCV001410826 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 307 of the ACVRL1 protein (p.Ala307Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 212800). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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