NM_024006.6(VKORC1):c.196G>A (p.Val66Met) AND Warfarin response

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 12, 2018
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:: RCV000853288.1

Allele description [Variation Report for NM_024006.6(VKORC1):c.196G>A (p.Val66Met)]

NM_024006.6(VKORC1):c.196G>A (p.Val66Met)

Gene:

VKORC1:vitamin K epoxide reductase complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p11.2

Genomic location:

Preferred name:

NM_024006.6(VKORC1):c.196G>A (p.Val66Met)

HGVS:

NC_000016.10:g.31093399C>T
NG_011564.1:g.6557G>A
NM_001311311.2:c.196G>A
NM_024006.6:c.196G>AMANE SELECT
NM_206824.3:c.173+1158G>A
NP_001298240.1:p.Val66Met
NP_076869.1:p.Val66Met
LRG_582t1:c.196G>A
LRG_582:g.6557G>A
LRG_582p1:p.Val66Met
NC_000016.9:g.31104720C>T
NC_000016.9:g.31104720C>T
NM_024006.5:c.196G>A

Protein change:

V66M

Links:

dbSNP: rs72547529

NCBI 1000 Genomes Browser:

rs72547529

Molecular consequence:

NM_206824.3:c.173+1158G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001311311.2:c.196G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024006.6:c.196G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Warfarin response
Synonyms:: COUMARIN SENSITIVITY; COUMARIN, POOR METABOLISM OF; WARFARIN RESISTANCE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007390; MedGen: C0750384; OMIM: 122700

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000996125	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 12, 2018) Condition: Warfarin response Drug reported used for: thrombosis	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000996125

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 12, 2018)
Condition: Warfarin response
Drug reported used for: thrombosis

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical 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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996125.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This variant has been previously reported in the literature in patients with warfarin resistance (PMID: 15630486). Functional studies demonstrate almost complete loss of activity for the p.Val66Met variant relative to wild type (PMID: 23039877). There are 70 reports of the variant as a heterozygous change in the population database, gnomAD, thus the variant is rare. The p.Val66Met residue is highly conserved among vertebrates, and the methionine substitution is predicted to be damaging by in silico models. Based on the combined evidence, the variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 16, 2025

ClinVar

Relating variation to medicine