NM_000552.5:c.8318G>C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4_ModeratePS3PP4_ModeratePS2_ModeratePP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.8318G>C variant in VWF is a missense variant predicted to cause substitution of cysteine by serine at amino acid 2773. This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patients with this variant displayed laboratory phenotypes of excessive mucocutaneous bleeding, very low VWF activity (measured by VWF:RCo assay), low VWF:RCo/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD Type 2A (PP4_moderate, PMID:17139364). This variant has been reported in 3 additional probands meeting type 2A laboratory criteria for PP4 (PS4_moderate; PMID:21979291, 32664776, 28971901), and one was a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID:32664776). Multimerization assay performed with the p.Cys2773Ser recombinant mutant and wild-type vWF co-expressed by HEK293 cells showed abnormal multimers (PMID:17139364 Fig. 2) that were counteracted by an allele-specific siRNA targeting the mutant transgene, indicating that this variant has a damaging effect on protein function (PMID:29734512)(PS3_supporting). The computational predictor REVEL gives a score of 0.876, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP4_Moderate, PS2_Moderate, PS4_Moderate, PS3, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228847/MONDO:0015628/081
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Von Willebrand disease type 2A Pathogenic:1
The NM_000552.5(VWF):c.8318G>C variant in VWF is a missense variant predicted to cause substitution of cysteine by serine at amino acid 2773. This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patients with this variant displayed laboratory phenotypes of excessive mucocutaneous bleeding, very low VWF activity (measured by VWF:RCo assay), low VWF:RCo/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD Type 2A (PP4_moderate, PMID: 17139364). This variant has been reported in 3 additional probands meeting type 2A laboratory criteria for PP4 (PS4_moderate; PMID: 21979291, 32664776, 28971901), and one was a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID: 32664776). Multimerization assay performed with the p.Cys2773Ser recombinant mutant and wild-type vWF co-expressed by HEK293 cells showed abnormal multimers (PMID: 17139364 Fig. 2) that were counteracted by an allele-specific siRNA targeting the mutant transgene, indicating that this variant has a damaging effect on protein function (PMID: 29734512)(PS3_supporting). The computational predictor REVEL gives a score of 0.876, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP4_Moderate, PS2_Moderate, PS4_Moderate, PS3, PP3, PM2_Supporting. -
not provided Other:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at