Submissions for variant NM_000020.3(ACVRL1):c.1445C>T (p.Ala482Val)

gnomAD frequency: 0.00203  dbSNP: rs139142865

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV000470977	SCV004805891	likely benign	Telangiectasia, hereditary hemorrhagic, type 2	2024-03-15	reviewed by expert panel	curation	The NM_000020.3: c.1445C>T variant in ACVRL1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 482 (p.Ala482Val). Another missense variant, c.1445C>A, Ala482Glu (PMID: 17786384, 21158752), in the same codon has been classified as likely pathogenic for autosomal dominant Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). However, the filtering allele frequency (the lower threshold of the 95% CI of 395/129122) of the c.1445C>T variant in ACVRL1 is 0.002819 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has also been observed in 3 patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ENG variant) (BP5; PMID: 15517393, Internal lab contributors). The computational predictor REVEL gives a score of 0.839, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ACVRL1 function (PP3). However, functional assays (BRE assay, Western blot analysis of Smad1/5 phosphorylation) in NIH-3T3 cells showed that the variant protein responded to BMP9 stimulation either measured in the BRE assay or by Smad1/5 phosphorylation, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 20501893). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP5, BS3_Supporting, PP3, PM5 (specification version 1.0.0; 1/4/2024).
GeneDx	RCV000766346	SCV000249625	likely benign	not provided	2020-04-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10323406, 15024723, 18285823, 24055113, 20501893, 25637381, 24082139, 15880681, 19767588, 15517393, 16690726, 15879500, 27316748)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000196441	SCV000538228	likely benign	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in multiple control cohorts; ExAC: 0.3% (190/66476) European chromosomes
Invitae	RCV000470977	SCV000562552	likely benign	Telangiectasia, hereditary hemorrhagic, type 2	2024-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000470977	SCV000602421	benign	Telangiectasia, hereditary hemorrhagic, type 2	2023-10-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000470977	SCV000743470	benign	Telangiectasia, hereditary hemorrhagic, type 2	2014-10-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000470977	SCV001272394	benign	Telangiectasia, hereditary hemorrhagic, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Genome-Nilou Lab	RCV000470977	SCV002524618	benign	Telangiectasia, hereditary hemorrhagic, type 2	2021-12-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390307	SCV002701531	likely benign	Cardiovascular phenotype	2017-06-22	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.
CeGaT Center for Human Genetics Tuebingen	RCV000766346	SCV004133338	benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	ACVRL1: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV004551293	SCV004733162	likely benign	ACVRL1-related disorder	2021-02-03	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
CSER _CC_NCGL, University of Washington	RCV000148353	SCV000190043	likely benign	Haemorrhagic telangiectasia 2	2014-06-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000470977	SCV000745688	likely benign	Telangiectasia, hereditary hemorrhagic, type 2	2016-11-09	no assertion criteria provided	clinical testing
Birmingham Platelet Group; University of Birmingham	RCV001270508	SCV001450807	uncertain significance	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000766346	SCV001800539	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766346	SCV001918244	likely benign	not provided		no assertion criteria provided	clinical testing
John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine	RCV002285146	SCV002575026	uncertain significance	Pulmonary arterial hypertension	2022-09-26	no assertion criteria provided	clinical testing