2-85552429-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5PP3_StrongPP5

The NM_000821.7(GGCX):​c.1426C>G​(p.Arg476Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R476C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

GGCX
NM_000821.7 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.28
Variant links:
Genes affected
GGCX (HGNC:4247): (gamma-glutamyl carboxylase) This gene encodes an integral membrane protein of the rough endoplasmic reticulum that carboxylates glutamate residues of vitamin K-dependent proteins to gamma carboxyl glutamate, a modification that is required for their activity. The vitamin K-dependent protein substrates have a propeptide that binds the enzyme, with carbon dioxide, dioxide, and reduced vitamin K acting as co-substrates. Vitamin K-dependent proteins affect a number of physiologic processes including blood coagulation, prevention of vascular calcification, and inflammation. Allelic variants of this gene have been associated with pseudoxanthoma elasticum-like disorder with associated multiple coagulation factor deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-85552429-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 2-85552429-G-C is Pathogenic according to our data. Variant chr2-85552429-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3335889.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GGCXNM_000821.7 linkuse as main transcriptc.1426C>G p.Arg476Gly missense_variant 10/15 ENST00000233838.9 NP_000812.2 P38435-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GGCXENST00000233838.9 linkuse as main transcriptc.1426C>G p.Arg476Gly missense_variant 10/151 NM_000821.7 ENSP00000233838.3 P38435-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251482
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461664
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Vitamin K-dependent clotting factors, combined deficiency of, type 1 Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchQiaoli Li laboratory, Thomas Jefferson University-The c.1426C>G, p.Arg476Gly variant has MAF less than 0.0007% in general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. While c.1426C>G, p.Arg476Gly, is not previously reported, two variants at the same amino acid, c.1426C>T, p.Arg476Cys, and c.1427G>A, p.Arg476His, have been previously reported as pathogenic variants in patients with PXE-like phenotypes with multiple coagulation factor deficiency (Vanakker et al., 2007, Watzka et al., 2014). Functional studies of the variant proteins at the same amino acid, p.Arg476Cys and p.Arg476His, demonstrate abolished carboxylation of vitamin K-dependent proteins, which is critical for blood coagulation, vascular calcification, and bone metabolism (Ghosh 2021, Hao 2021). Based on available information, the c.1426C>G, p.Arg476Gly variant is considered likely pathogenic. REFERENCES Ghosh S et al. GGCX mutations show different responses to vitamin K thereby determining the severity of the hemorrhagic phenotype in VKCFD1 patients. 2021 Jun;19(6):1412-1424. PMID: 33590680. Hao Z et al. γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins. 2021 Jan 28;137(4):533-543. PMID: 33507293. Vanakker et al. Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J Invest Dermatol, 127, 581-7. Watzka et al. Bleeding and non-bleeding phenotypes in patients with GGCX gene mutations. Thromb Res, 134, 856-65. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
M;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-6.6
D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.94
MutPred
0.83
Loss of helix (P = 0.0123);.;
MVP
0.90
MPC
1.1
ClinPred
0.90
D
GERP RS
6.0
Varity_R
0.92
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121909681; hg19: chr2-85779552; API