Submissions for variant NM_000020.3(ACVRL1):c.1069C>T (p.Gln357Ter)

dbSNP: rs2139075900

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388096	SCV001588948	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2022-02-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln357*) 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: 15712271). ClinVar contains an entry for this variant (Variation ID: 1074703). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001388096	SCV002766868	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary haemorrhagic telangiectasia type 2 (MIM# 600376) (PMID: 16282348; 26176610). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity and are commonly reported in families with hereditary haemorrhagic telangiectasia type 2 (ClinVar; PMID: 15879500). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in unrelated probands with hereditary haemorrhagic telangiectasia type 2 and has been classified as pathogenic (VCGS, ClinVar, PMIDs: 15712271, 34872578). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
deCODE genetics, Amgen	RCV001388096	SCV004022109	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2023-07-21	no assertion criteria provided	research	The variant NM_000020.3:c.1069C>T (chr12:51916056) in ACVRL1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2, PP5) this variant classifies as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004550099	SCV004718765	pathogenic	ACVRL1-related disorder	2024-02-08	no assertion criteria provided	clinical testing	The ACVRL1 c.1069C>T variant is predicted to result in premature protein termination (p.Gln357*). This variant has been reported in individuals with hereditary hemorrhagic telangiectasia (see for example - Abdalla et al. 2005. PubMed ID: 15712271; Kitayama et al. 2021. PubMed ID: 34872578). 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.