Submissions for variant NM_000552.5(VWF):c.6104G>A (p.Gly2035Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	RCV004821327	SCV005442527	uncertain significance	Hereditary von Willebrand disease	2024-08-13	reviewed by expert panel	curation	NM_000552.5:c.6104G>A is a missense variant in VWF that replaces glycine with aspartic acid at position 2035. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.003657 (based on 186/44882 alleles in the East Asian population, with 2 homozygotes), which is between the ClinGen VWD VCEP thresholds for BS1 (>0.01) and PM2_Supporting (<0.0001), failing to meet either criterion. This variant has been reported in the heterozygous state in at least one patient with a mildly abnormal bleeding score and reduced quantity of von Willebrand factor, which together are consistent with but not highly specific for VWD Type 1 (PMID: 28536718). This variant also has been reported in at least 1 individual with VWD Type 3, who was compound heterozygous for the variant in trans with the NM_000552.5(VWF):c.3365C>T (p.Thr1122Met) variant. PM3 was not considered due to the absence of phenotype details to confirm the diagnosis (PMID: 34490048). The computation predictor REVEL gives a score of 0.071, which is below the ClinGen VWD VCEP BP4 threshold of <0.290 and does not predict a damaging effect on VWF function. However, the computational splicing predictor SpliceAI gives the variant a delta score of 0.13 for splice donor gain, indicating an inconclusive impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the absence of any ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002308556	SCV002600434	likely benign	not specified	2022-10-11	criteria provided, single submitter	clinical testing	Variant summary: VWF c.6104G>A (p.Gly2035Asp) results in a non-conservative amino acid change located in the 4th type D domain (IPR001846) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251228 control chromosomes in the gnomAD database, including 2 homozygotes. However the variant is reported with even higher allele frequencies in several East Asian subpopulations, including the Japanese (0.0014 in the jMorp database), Chinese (0.0046 in ChinaMAP), and Vietnamese (0.016 in the Vietnamese-KHV, Le_2019), suggesting that the variant might be benign. The variant, c.6104G>A, has been reported in the literature in 3 Chinese individuals affected with a mild type 1 Von Willebrand Disease, however without providing supporting evidence for causality (Liang_2017). This report does not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.