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NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu) AND VWF-related condition

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 8, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003924788.1

Allele description

NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

Gene:
VWF:von Willebrand factor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p13.31
Genomic location:
Preferred name:
NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
Other names:
p.P1266L
HGVS:
  • NC_000012.12:g.6019621G>A
  • NG_009072.2:g.110050C>T
  • NM_000552.5:c.3797C>TMANE SELECT
  • NM_000552.5:c.3797C>T
  • NP_000543.2:p.Pro1266Leu
  • NP_000543.3:p.Pro1266Leu
  • LRG_587t1:c.3797C>T
  • LRG_587:g.110050C>T
  • LRG_587p1:p.Pro1266Leu
  • NC_000012.11:g.6128787G>A
  • NC_000012.12:g.6019621G>A
  • NG_009072.1:g.110050C>T
  • NM_000552.2:c.3797C>T
  • NM_000552.3:c.3797C>T
  • NM_000552.4:c.3797C>T
  • P04275:p.Pro1266Leu
Protein change:
P1266L; PRO1266LEU
Links:
UniProtKB: P04275#VAR_005791; OMIM: 613160.0033; dbSNP: rs61749370
NCBI 1000 Genomes Browser:
rs61749370
Molecular consequence:
  • NM_000552.5:c.3797C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
VWF-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004743917PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Dec 8, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004743917.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The VWF c.3797C>T variant is predicted to result in the amino acid substitution p.Pro1266Leu. (aka VWD2B Malmo/New York). This variant, and a similar variant, p.Pro1266Gln, have been reported in patients with autosomal dominant VWD types 1 or 2 (type 2B in Veyradier et al. 2016. PubMed ID: 26986123 and Freitas. 2019. PubMed ID: 30817071; aka p.Pro503Leu, type I New York or type II Malmo in Holmberg et al. 1993. PubMed ID: 8486782; Federici et al. 2009. PubMed ID: 18805962; Ahmad et al. 2013. PubMed ID: 23179108). The p.Pro1266Leu and p.Pro1266Gln substitutions are characterized by enhanced ristocetin-induced platelet aggregation (RIPA), low bleeding severity, normal VWF multimer formation, and no thrombocytopenia in most of the patients harboring one of these two variants (Holmberg et al. 1993. PubMed ID: 8486782; Federici et al. 2009. PubMed ID: 18805962). Several patients with one of these variants were shown to have slightly elevated bleeding severity and the p.Pro1266Leu substitution was reported to enhance the VWF—GP1B protein interaction (Gupta et al. 2005. PubMed ID: 16115133) suggesting that substitutions of p.Pro1266 are unlikely to be benign and are likely to be a primary cause of disease. This variant is reported in 0.37% of alleles in individuals of European (Finnish) descent in gnomAD, however this is a region with high homology to other sites in the genome so allele frequency data may not be representative. This variant is interpreted as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024