Submissions for variant NM_000020.3(ACVRL1):c.1246+9C>T

gnomAD frequency: 0.00958  dbSNP: rs115378744

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000249414	SCV000301533	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000456288	SCV000379834	benign	Telangiectasia, hereditary hemorrhagic, type 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000456288	SCV000562553	benign	Telangiectasia, hereditary hemorrhagic, type 2	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000249414	SCV000711278	benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	1246+9C>T in intron 8 of ACVRL1: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 2.7% (121/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs115378744).
GeneDx	RCV000249414	SCV000714198	benign	not specified	2017-02-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000249414	SCV001774675	benign	not specified	2021-07-09	criteria provided, single submitter	clinical testing	Variant summary: ACVRL1 c.1246+9C>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0023 in 247898 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 68.98 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. To our knowledge, no occurrence of c.1246+9C>T in individuals affected with Hereditary Hemorrhagic Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000456288	SCV002524602	benign	Telangiectasia, hereditary hemorrhagic, type 2	2021-12-05	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000249414	SCV001921854	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000249414	SCV001929726	benign	not specified		no assertion criteria provided	clinical testing