ClinVar Genomic variation as it relates to human health

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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1074703). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15712271). This variant is not present in population databases (gnomAD no frequency).

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

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.

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.