NM_000821.7(GGCX):c.1454G>C (p.Arg485Pro) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 24, 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:: RCV003556035.2

Allele description [Variation Report for NM_000821.7(GGCX):c.1454G>C (p.Arg485Pro)]

NM_000821.7(GGCX):c.1454G>C (p.Arg485Pro)

Gene:

GGCX:gamma-glutamyl carboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p11.2

Genomic location:

Preferred name:

NM_000821.7(GGCX):c.1454G>C (p.Arg485Pro)

HGVS:

NC_000002.12:g.85551967C>G
NG_011811.2:g.14568G>C
NM_000821.7:c.1454G>CMANE SELECT
NM_001142269.4:c.1283G>C
NP_000812.2:p.Arg485Pro
NP_001135741.1:p.Arg428Pro
LRG_592t1:c.1454G>C
LRG_592:g.14568G>C
LRG_592p1:p.Arg485Pro
NC_000002.11:g.85779090C>G
P38435:p.Arg485Pro

Protein change:

R428P; ARG485PRO

Links:

UniProtKB: P38435#VAR_021826; OMIM: 137167.0003; dbSNP: rs121909676

NCBI 1000 Genomes Browser:

rs121909676

Molecular consequence:

NM_000821.7:c.1454G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142269.4:c.1283G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004292614	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15287948, 16905958, 27394683, 34816548, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004292614

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 24, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors.

Rost S, Fregin A, Koch D, Compes M, Müller CR, Oldenburg J.

Br J Haematol. 2004 Aug;126(4):546-9.

PubMed [citation]

PMID:: 15287948

Founder mutation Arg485Pro led to recurrent compound heterozygous GGCX genotypes in two German patients with VKCFD type 1.

Rost S, Geisen C, Fregin A, Seifried E, Müller CR, Oldenburg J.

Blood Coagul Fibrinolysis. 2006 Sep;17(6):503-7.

PubMed [citation]

PMID:: 16905958

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004292614.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 485 of the GGCX protein (p.Arg485Pro). This variant is present in population databases (rs121909676, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive vitamin K-dependent clotting factors deficiency (PMID: 15287948, 16905958, 34816548). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 16197). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GGCX function (PMID: 27394683, 34816548). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024

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