Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000552.5(VWF):c.4693G>T (p.Val1565Leu)

CA6402474

256682 (ClinVar)

Gene: VWF

Condition: hereditary von Willebrand disease

Inheritance Mode: Undetermined mode of inheritance

Link to MONDO

UUID: 144492b5-a882-4895-b681-684b0c0d477c

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.4693G>T

NM_000552.5(VWF):c.4693G>T (p.Val1565Leu)

NC_000012.12:g.6018725C>A

CM000674.2:g.6018725C>A

NC_000012.11:g.6127891C>A

CM000674.1:g.6127891C>A

NC_000012.10:g.5998152C>A

NG_009072.1:g.110946G>T

NG_009072.2:g.110946G>T

ENST00000261405.10:c.4693G>T

ENST00000261405.9:c.4693G>T

ENST00000538635.5:n.421-24791G>T

NM_000552.3:c.4693G>T

NM_000552.4:c.4693G>T

Benign

BA1 BP4

PP4 BP2 BP5

Evidence Links 0

Expert Panel

von Willebrand Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

von Willebrand Disease VCEP

The NM_000552.4(VWF):c.4693G>T (p.Val1565Leu) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 is 0.3882 (based on 17604/44790 alleles in the east Asian population, including 3463 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. The computational predictor REVEL gives a score of 0.183, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4.

BA1

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.3882 (based on 17604/44790 alleles in the east Asian population, including 3463 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1.

BP4

The computational predictor REVEL gives a score of 0.183, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing.

PP4

31 individuals heterozygous for the V1565L SNP were studied (VWF:Ag 117±40% and VWF:CB 79±27% were measured and multimers analyzed) and were not affected by VWD.

BP2

At least one VWD type 2A proband has been reported (PMID: 30762591) with V1565L in cis or trans with the additional vWF variant D1498G (Clinvar 618486, VUS) which is suspected to be the causative variant. The D1498 variant has not yet been assessed by the VWD VCEP so BP2 is not applied.

BP5

9 Index cases with various (unspecified) bleeding disorders were found to carry the V1565L SNP (as well as 10 controls). The alternate basis of disease was not reported for this individuals.

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