Submissions for variant NM_000552.5(VWF):c.3970G>A (p.Gly1324Ser)

gnomAD frequency: 0.00001  dbSNP: rs61749398

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	RCV000000327	SCV005442537	pathogenic	von Willebrand disease type 2M	2024-08-13	reviewed by expert panel	curation	The NM_000552.4(VWF):c.3970G>A (p.Gly1324Ser) variant is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 1324. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and a decreased GP1b binding assay, which together are highly specific for VWD type 2M (PP4_moderate, PMID: 30084138). The variant has been reported to segregate with VWD type 2M through 2 affected meioses from 1 family (PP1; PMID: 29341351). At least 3 additional VWD type 2M probands have been reported with this variant (PMIDs: 29341351, 22102201, 1409710; PS4_moderate). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000003650 (based on 2/91074 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.718, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A platelet binding assay in COS-7 cells expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function. In a direct binding assay, the ristocetin-induced binding of rvWF(G1324S) to platelets was markedly reduced compared with rvWF(wt). (PMID: 1409710) (PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP1, PP3, PP4_moderate, PS4_moderate. (VCEP specifications version Pilot; date of approval).
Genetics and Molecular Pathology, SA Pathology	RCV003447468	SCV004175490	pathogenic	von Willebrand disease type 2	2021-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086716	SCV004221525	likely pathogenic	not provided	2023-05-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/250604 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with Type 2B and Type 2M VWD (PMIDs: 29341351 (2018), 27761512 (2016), 25185554 (2014), 22102201 (2011), and 1409710 (1992)). Functional studies demonstrated that this variant is damaging to protein function (PMIDs: 29341351 (2018), 27761512 (2016), 25185554 (2014), and 1409710 (1992)). 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 likely pathogenic.
OMIM	RCV000000327	SCV000020471	pathogenic	von Willebrand disease type 2M	2010-05-01	no assertion criteria provided	literature only
Academic Unit of Haematology, University of Sheffield	RCV000086716	SCV000118921	not provided	not provided		no assertion provided	not provided