Submissions for variant NM_000020.3(ACVRL1):c.890A>G (p.His297Arg)

gnomAD frequency: 0.00011  dbSNP: rs139380315

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455714	SCV000538229	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Published as VUS; ExAC: 3/11550 Latino chromosomes
Labcorp Genetics (formerly Invitae), Labcorp	RCV001246199	SCV001419539	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 2	2021-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 297 of the ACVRL1 protein (p.His297Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs139380315, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This missense change has been observed in individual(s) with ACVRL1-related conditions (PMID: 6470589, 19767588). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 161204). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002371987	SCV002685565	likely benign	Cardiovascular phenotype	2024-10-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV003227674	SCV003924729	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	Has been reported as a variant of uncertain significance in a patient and other affected family members with HHT that also harbored a p.(C344R) variant in the ACVRL1 gene (McDonald et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24055113, 25637381, 16705692, 19767588, 16470589)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455714	SCV005040152	likely benign	not specified	2024-03-06	criteria provided, single submitter	clinical testing	Variant summary: ACVRL1 c.890A>G (p.His297Arg) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251252 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in ACVRL1 causing Hereditary Hemorrhagic Telangiectasia phenotype (3.3e-05), strongly suggesting that the variant is benign. c.890A>G has been reported in the literature in individuals from a family affected with Hereditary Hemorrhagic Telangiectasia, without pedigree and co-occurring information for further analysis (example, Fernandez_2006), this variant also did not segregate with disease in a subsequent study (McDonald_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Hemorrhagic Telangiectasia. Co-occurrences with other pathogenic variant(s) have been reported in an individual affected with epistaxis (ACVRL1 c.1030T>C , p.Cys344Arg), providing supporting evidence for a benign role (McDonald_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 24055113, 16470589, 19767588). ClinVar contains an entry for this variant (Variation ID: 161204). Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV001246199	SCV005637352	likely benign	Telangiectasia, hereditary hemorrhagic, type 2	2024-02-25	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148357	SCV000190047	uncertain significance	Haemorrhagic telangiectasia 2	2014-06-01	no assertion criteria provided	research