rs121909678

Variant names:

• chr2-85551548-C-T
• rs121909678
• NM_000821.7:c.1672G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000821.7(GGCX):​c.1672G>A​(p.Gly558Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GGCX NM_000821.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.17
• Publications: 8 publications found

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]

GGCX Gene-Disease associations (from GenCC):

• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 2-85551548-C-T is Pathogenic according to our data. Variant chr2-85551548-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16200.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7	c.1672G>A	p.Gly558Arg	missense_variant	Exon 12 of 15	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.1672G>A	p.Gly558Arg	missense_variant	Exon 12 of 15	1	NM_000821.7	ENSP00000233838.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00220 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency Pathogenic:1

Mar 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.0	M;.
PhyloP100		7.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.86		Gain of helix (P = 0.0078);.;
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.93
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909678; hg19: chr2-85778671;