Submissions for variant NM_000020.3(ACVRL1):c.841G>T (p.Glu281Ter)

dbSNP: rs779485996

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465534	SCV000552407	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu281*) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 20414677; internal data database, internal datadatabase). ClinVar contains an entry for this variant (Variation ID: 411307). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000578762	SCV000681034	pathogenic	not provided	2017-08-31	criteria provided, single submitter	clinical testing	The E281X variant in the ACVRL1 gene has been reported at least two patients with HHT, both of these patients also harbored ACVRL1 c.1049-1 G>A and these variants were on the same allele of the ACVRL1 gene (in cis) in one of these patients (Richards-Yutz et al., 2010; SCV000552407.1; Landrum et al., 2016). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the ACVRL1 gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014). Furthermore, the E281X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics	RCV004992242	SCV005545946	pathogenic	Cardiovascular phenotype	2024-09-04	criteria provided, single submitter	clinical testing	The p.E281* pathogenic mutation (also known as c.841G>T), located in coding exon 6 of the ACVRL1 gene, results from a G to T substitution at nucleotide position 841. This changes the amino acid from a glutamic acid to a stop codon within coding exon 6. This variant co-occurred with ACVRL1 c.1049-1G>A in an individual with hereditary hemorrhagic telangiectasia (Richards-Yutz J et al. Hum Genet, 2010 Jul;128:61-77). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV004722791	SCV005338693	pathogenic	ACVRL1-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The ACVRL1 c.841G>T variant is predicted to result in premature protein termination (p.Glu281*). This variant, along with the ACVRL1 c.1049-1G>A variant, was reported in an individual with hereditary hemorrhagic telangiectasia (Richards-Yutz et al. 2010. PubMed ID: 20414677). It was suggested that the c.841G>T and c.1049-1G>A variants were likely on the same allele; however, no additional studies were conducted to determine phase. This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ACVRL1 are expected to be pathogenic. This variant is interpreted as pathogenic.