Von Willebrand-disease_ a patient with a variant of uncertain significance: phenotype like type 1, genotype like type 3

Introduction We report about a 32 year old women presenting first in 3/2019 due to severe menstrual bleeding, easy bruising, prolonged wound healing.

Testing of DDVAP showed good effectiveness and tranexamic acid was started for the severe menstrual bleeding.

In August 2019 presented in hospital due to vaginal bleedings during pragnancy caused by a retroplancental haematoma. An caesarian section was necessary due bleedings (39. gestational week), postpartal she required transfusion..

Method Von Willebrand-factor activity, -antigen und CBA were measured on ACL AcuStar, Werfen, Germany (HaemoIL).

FVIIIc activity on BCS, Siemens, Germany (fviii deficient plasma).

Multimer analysis was performed by Synlab, Regensburg.

Genetic testing via NGS (illumina; NextSeg)

Results One year later the patient presented with severe menstrual bleeding, neither DDVAP nor tranexamic acid helped..

For the first time the patient recognised pain in her right knee- due to joint bleeds.

We started an on-demand treatment with von Willebrand-factor concentrate during the period of the severe menstrual bleeding (homecare service.

Because the bleeding severity did not match to the vWF levels/multimer analysis we did a genetic testing.

Genetic testing: variant of uncertain significance ACMG class 3:

NM_000552.4:c.5170 10C>T.Intron 29 and NM_000552.4:c.6652C>T. Exon38 p.(Arg2218Trp).

heterozygous (dbSNP;rs61750601.HGMD:CS002689

Conclusion Variant c.5170, 10C > T has been described several times in the literature, but there is no matching evaluation regarding clinical relevance.

Borras et al (1) detected this mutation in patients with Von Willebrand type 3 in a compound-heterozygous form. In a study by Corrales et al (2), however, no visible effect on splicing site could be shown.

Table 1 (lab results).

Date	FVIIIc (%)	VWF:Ag (%)	VWF:act (%)	VWF:CBA (%)	Ratio	Multimers
19,03,2019	97	47	43	68	0,9	Not poss to evaluate
13.05.2019	337	175	197	2013	1,1	nd
After DDVAP
16.03.2022	222	151	172	191	1,2	nd
End of pregnancy
13.52020 (5 weeks after birth)	111	55	54	77	1.1	Not poss to evaluate

The ClinVar database currently regards the variant as conflicting, because there are assessments as „likely benign“ and „variant with uncertain significance“. Baroncino et al (3), associated it with a von Willebrand type 3 in the ISTH SCC VWF database.[1] [2] [3]

Further, variant c6652C > T. p.Arg2218Trp in heterozygous form could be detected in exon 38 of the VWF gene.

This mutation is listed only 6 times in the gnomAD database. However, so far it is not listed in the databases NCBI ClinVaar, LOVD, HGMD and ISTH-SSC VWF ([Table 1]).

The REVEL score (Rare Exome Variant Ensemble Lerner), which relies on several predictive programs, is 0.542 in the variant, with a score of more than 0.5 indicating a presumed cause of disease of a variant.

Due to this data situation, the variant must be classified as a variant with uncertain significance. On demand treatment with vWF-concentrate is a way for the patient to prevent bleeding.

Publikationsverlauf

Artikel online veröffentlicht:
20. Februar 2023

• References

• 1 Borras N. et al Molecular and clinical profile of VWD in Spain : comprehensive geneticalnalsyis by next -geneting sequencing of 480 patients. Haematologica 2017; 102 (12) 2005-2014
• 2 LCorrales I, et al The study oft he effect of splicing mutations in von Willebrand factor using RNA isolated form patients`platelets and leukocystes. J Thromb Haemost 2011; 9 (04) 679-688
• 3 Baronciani L. et al Molecular characterization of a multiethnic group of 21 patients with type 3 von Willebrand-disease. Thromb Haemost 2000; 84: 536-540