chr12-6019297-C-A
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000552.5(VWF):c.4121G>T(p.Arg1374Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1374C) has been classified as Pathogenic.
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461642Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0AN XY: 727132
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with von Willebrand Disease, Types 2A or 2M (PMIDs: 30046717 (2017), 26986123 (2016), 19277422 (2009), 17408416 (2007), 9198195 (1997)), and 2 other known pathogenic variants affect the same amino acid (PMID: 11843298 (2002)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
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PP3, PP5, PM2, PM5, PS4_moderate -
Hereditary von Willebrand disease Pathogenic:2
Variant summary: VWF c.4121G>T (p.Arg1374Leu) results in a non-conservative amino acid change located in a type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250960 control chromosomes (gnomAD). c.4121G>T has been reported in the literature in multiple individuals affected with Von Willebrand Disease (e.g., Meyer_1997, Veyradier_2007, Gadisseur_2009, Veyradier_2016, Borras_2017, Kim_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28971901, 19506361, 9198195, 17408416, 26986123, 31240882). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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von Willebrand disease type 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at