ClinVar Genomic variation as it relates to human health
NM_000821.7(GGCX):c.763G>A (p.Val255Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000821.7(GGCX):c.763G>A (p.Val255Met)
Variation ID: 16206 Accession: VCV000016206.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p11.2 2: 85554269 (GRCh38) [ NCBI UCSC ] 2: 85781392 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 19, 2017 Mar 11, 2023 Mar 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000821.7:c.763G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000812.2:p.Val255Met missense NM_000821.5:c.763G>A NM_001142269.4:c.592G>A NP_001135741.1:p.Val198Met missense NC_000002.12:g.85554269C>T NC_000002.11:g.85781392C>T NG_011811.2:g.12266G>A LRG_592:g.12266G>A LRG_592t1:c.763G>A LRG_592p1:p.Val255Met - Protein change
- V255M, V198M
- Other names
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- Canonical SPDI
- NC_000002.12:85554268:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GGCX | - | - |
GRCh38 GRCh37 |
448 | 481 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2009 | RCV000017590.30 | |
not provided (1) |
no classification provided
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- | RCV001824572.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 2, 2023 | RCV001851893.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002176496.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 255 of the GGCX protein (p.Val255Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 255 of the GGCX protein (p.Val255Met). This variant is present in population databases (rs121909683, gnomAD 0.009%). This missense change has been observed in individuals with GGCX-related conditions (PMID: 18800149, 28125048, 33000479, 34906475). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16206). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GGCX function (PMID: 18800149, 33507293, 34816548). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003837281.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
Observed with an additional GGCX variant on the opposite allele (in trans) in siblings with features suggestive of pseudoxanthoma elasticum(PXE)-like disorder with multiple coagulation factor … (more)
Observed with an additional GGCX variant on the opposite allele (in trans) in siblings with features suggestive of pseudoxanthoma elasticum(PXE)-like disorder with multiple coagulation factor deficiency; other affected individuals in this family had the p.(V255M) variant as well as a pathogenic variant in the ABCC6 gene which is known to cause PXE, suggesting possible digenic inheritance (Li et al., 2009); Identified in patients with pulmonary arterial hypertension in published literature, but additional clinical information and familial segregation information were not provided (Zhu N et al., 2019); Published functional studies suggest this variant results in impairment of enzyme activity, however the exact mechanism of enzyme-substrate interaction is not well established (Li et al., 2009; Rishavy et al., 2012; Hao et al., 2021; Rishavy et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22516721, 35628569, 21453708, 33507293, 35767717, 28125048, 34816548, 18800149, 34906475, 33000479, 31727138) (less)
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Pathogenic
(Mar 01, 2009)
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no assertion criteria provided
Method: literature only
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PXE-LIKE DISORDER WITH MULTIPLE COAGULATION FACTOR DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037862.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2017 |
Comment on evidence:
In 2 sisters with a pseudoxanthoma elasticum (PXE)-like disorder and multiple coagulation factor deficiency (610842), Li et al. (2009) identified compound heterozygosity for a 791G-A … (more)
In 2 sisters with a pseudoxanthoma elasticum (PXE)-like disorder and multiple coagulation factor deficiency (610842), Li et al. (2009) identified compound heterozygosity for a 791G-A transition in exon 7 of the GGCX gene, resulting in a val255-to-met (V255M) substitution, and a 927C-T transition in exon 8 of the GGCX gene, resulting in a ser300-to-phe (S300F; 137167.0013) substitution. Neither mutation was identified in 100 control alleles. Val255 was highly conserved, whereas ser300 was less well conserved. The sisters showed milder coagulation factor defects than previously reported patients, suggesting some residual GGCX activity. In vitro functional expression studies using a small peptide showed that the V255M mutant had about 5% residual GGCX activity and the S300F variant had essentially no activity. However, when present with a factor X propeptide, the V255M mutant showed GGCX activity similar to wildtype, whereas the S300F mutant activity remained low at 3% of wildtype. Skin biopsies from the patients showed undercarboxylated matrix gla proteins (MGP; 154870) in the areas of abnormal mineralization. The family was unusual in that the sisters' mother and maternal aunt had mild PXE-like skin changes, but no coagulopathy. Skin biopsies in the mother and aunt showed undercarboxylated MGP in the areas of abnormal mineralization. Genetic analysis showed compound heterozygosity for the V255M mutation and a common mutation in the ABCC6 gene (R1141X; 603234.0001), which can cause classic PXE (264800) when present with another ABCC6 mutation, but not in isolation. The findings suggested that the mother and aunt had digenic inheritance of a 'forme fruste' of PXE (177850). In contrast, the unaffected father and brother, who were compound heterozygous for the S300F mutation and the ABCC6 R1141X mutation had no signs of either disorder on clinical exam but refused to participate in further clinical testing. Plasma levels of total undercarboxylated MGP in the father and son were at the lower end of normal. Although the reasons for the lack of clinical findings in the father and son remained unclear, Li et al. (2009) concluded that undercarboxylation of MGP plays a critical role in aberrant mineralization of tissues in PXE. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Vitamin K-dependent clotting factors, combined deficiency of, type 1
Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency
Affected status: unknown
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV002074948.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant interpreted as not provided and reported on 07-02-2014 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpreted as not provided and reported on 07-02-2014 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormal delivery (present) , Overgrowth (present) , Short stature (present) , Failure to thrive (present) , Delayed puberty (present) , Abnormal facial shape (present) , … (more)
Abnormal delivery (present) , Overgrowth (present) , Short stature (present) , Failure to thrive (present) , Delayed puberty (present) , Abnormal facial shape (present) , Abnormal oral cavity morphology (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Abnormal skull morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Myopia (present) , Hypermetropia (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Memory impairment (present) , Autistic behavior (present) , Anxiety (present) , Short attention span (present) , Hyperextensible skin (present) , Joint hypermobility (present) , Pectus excavatum (present) , Skeletal dysplasia (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Tooth malposition (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2014-07-02
Testing laboratory interpretation: not provided
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort. | Saeidian AH | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906475 |
GGCX variants leading to biallelic deficiency to γ-carboxylate GRP cause skin laxity in VKCFD1 patients. | Ghosh S | Human mutation | 2022 | PMID: 34816548 |
γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins. | Hao Z | Blood | 2021 | PMID: 33507293 |
GGCX mutations in a patient with overlapping pseudoxanthoma elasticum/cutis laxa-like phenotype. | Li D | The British journal of dermatology | 2021 | PMID: 33000479 |
GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations. | De Vilder EY | International journal of molecular sciences | 2017 | PMID: 28125048 |
Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes. | Li Q | The Journal of investigative dermatology | 2009 | PMID: 18800149 |
Text-mined citations for rs121909683 ...
HelpRecord last updated Mar 11, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.