Submissions for variant NM_000020.3(ACVRL1):c.924C>A (p.Cys308Ter)

dbSNP: rs1555153131

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542741	SCV000639410	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys308*) 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 (HHT) (PMID: 9245985, 16123970). ClinVar contains an entry for this variant (Variation ID: 464771). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000598771	SCV000709907	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published studies in patient cells support this variant results in nonsense mediated decay (PMID: 9245985); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16123970, 16429404, 17786384, 23066781, 33919892, 9245985)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000598771	SCV000884966	pathogenic	not provided	2018-03-29	criteria provided, single submitter	clinical testing	The ACVRL1 c.924C>A; p.Cys308Ter variant is reported in the literature in individuals with HHT (Bayrak-Toydemir 2004, Berg 1997, Lenato 2006, Olivieri 2007), and classified as pathogenic in ClinVar (Variation ID: 464771). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered pathogenic. REFERENCES Bayrak-Toydemir P et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med. 2004 Jul-Aug;6(4):175-91. Berg JN et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7. 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. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9.
Mayo Clinic Laboratories, Mayo Clinic	RCV000598771	SCV001713601	pathogenic	not provided	2019-07-08	criteria provided, single submitter	clinical testing	PVS1, PS4_Moderate, PM2
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000542741	SCV002061768	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2021-11-24	criteria provided, single submitter	clinical testing	PVS1, PP1, PM2
MGZ Medical Genetics Center	RCV000542741	SCV002580268	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2021-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002377081	SCV002688297	pathogenic	Cardiovascular phenotype	2021-03-11	criteria provided, single submitter	clinical testing	The p.C308* pathogenic mutation (also known as c.924C>A), located in coding exon 6 of the ACVRL1 gene, results from a C to A substitution at nucleotide position 924. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This mutation has been detected in individuals with hereditary hemorrhagic telangiectasia, including multiple affected relatives from one family (Berg JN et al. Am J Hum Genet, 1997 Jul;61:60-7; Argyriou L et al. Liver Transpl, 2005 Sep;11:1132-5; Olivieri C et al. J Hum Genet, 2007 Sep;52:820-829). In addition, the transcript carrying this mutation could not be detected by RT-PCR using mRNA isolated from peripheral blood leukocytes (Berg JN et al. Am J Hum Genet, 1997 Jul;61:60-7). In addition to the clinical data presented in the literature, 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.