VCV002682121.3 - ClinVar

NM_000552.5(VWF):c.5483G>T (p.Gly1828Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000552.5(VWF):c.5483G>T (p.Gly1828Val)

Variation ID: 2682121 Accession: VCV002682121.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.31 12: 6013618 (GRCh38) [ NCBI UCSC ] 12: 6122784 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 6, 2024	Nov 24, 2024	May 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000552.5:c.5483G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000543.3:p.Gly1828Val	missense
NC_000012.12:g.6013618C>A
NC_000012.11:g.6122784C>A
NG_009072.2:g.116053G>T
LRG_587:g.116053G>T
LRG_587t1:c.5483G>T	LRG_587p1:p.Gly1828Val

... more HGVS ... less HGVS

Protein change

G1828V

Other names

p.Gly1828Val

Canonical SPDI

NC_000012.12:6013617:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
VWF		-	-	GRCh38 GRCh37	1594	1648

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 27, 2023	RCV003477413.2
not specified	Uncertain significance (1)	criteria provided, single submitter	May 21, 2024	RCV004690418.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Sep 12, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004221556.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 35343054 Comment: In the published literature, this variant has been reported in an individual with type 3 von Willebrand disease (VWD) (PMID: 35343054 (2022)). The frequency of … (more) In the published literature, this variant has been reported in an individual with type 3 von Willebrand disease (VWD) (PMID: 35343054 (2022)). The frequency of this variant in the general population, 0.000004 (1/251232 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (May 21, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005185144.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 35343054 Comment: Variant summary: VWF c.5483G>T (p.Gly1828Val) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded … (more) Variant summary: VWF c.5483G>T (p.Gly1828Val) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251232 control chromosomes. c.5483G>T has been reported in the literature in at least two individuals affected with Von Willebrand Disease (eg., Christopherson_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35343054). ClinVar contains an entry for this variant (Variation ID: 2682121). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Uncertain significance (Nov 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408221.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 35343054 Comment: PP3, PM1_supporting, PM2_moderate Number of individuals with the variant: 1

Comment:

In the published literature, this variant has been reported in an individual with type 3 von Willebrand disease (VWD) (PMID: 35343054 (2022)). The frequency of this variant in the general population, 0.000004 (1/251232 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant.

Comment:

Variant summary: VWF c.5483G>T (p.Gly1828Val) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251232 control chromosomes. c.5483G>T has been reported in the literature in at least two individuals affected with Von Willebrand Disease (eg., Christopherson_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35343054). ClinVar contains an entry for this variant (Variation ID: 2682121). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program.	Christopherson PA	Journal of thrombosis and haemostasis : JTH	2022	PMID: 35343054

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000552.5(VWF):c.5483G>T (p.Gly1828Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...