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
Consequence
NM_000821.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GGCX | NM_000821.7 | c.1426C>G | p.Arg476Gly | missense_variant | 10/15 | ENST00000233838.9 | NP_000812.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GGCX | ENST00000233838.9 | c.1426C>G | p.Arg476Gly | missense_variant | 10/15 | 1 | NM_000821.7 | ENSP00000233838.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251482Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461664Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727148
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Vitamin K-dependent clotting factors, combined deficiency of, type 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Qiaoli 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at