ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1321G>A (p.Val441Met) (rs1565596498)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755786 SCV000883358 likely pathogenic not provided 2018-04-22 criteria provided, single submitter clinical testing The ACVRL1 c.1321G>A; p.Val441Met variant is reported in the literature in families with HHT (Abdalla 2005, Lenato 2006, Yuan 2015). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 441 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005 Mar;25(3):320-1. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Yuan D et al. Gene analysis in a family of hereditary hemorrhagic telangiectasia. Zhonghua Xue Ye Xue Za Zhi. 2015 Feb;36(2):112-5.
Invitae RCV001058165 SCV001222714 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-03-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 441 of the ACVRL1 protein (p.Val441Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hereditary hemorrhagic telangiectasia in a family (PMID: 25778885) and has been observed in individuals affected with this condition (PMID: 15712271, 16429404, 26176610). ClinVar contains an entry for this variant (Variation ID: 617960). This variant has been reported to affect ACVRL1 protein function (PMID: 26176610). For these reasons, this variant has been classified as Pathogenic.

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