ClinVar Genomic variation as it relates to human health
NM_000089.4(COL1A2):c.838G>A (p.Gly280Ser)
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_000089.4(COL1A2):c.838G>A (p.Gly280Ser)
Variation ID: 35957 Accession: VCV000035957.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q21.3 7: 94409367 (GRCh38) [ NCBI UCSC ] 7: 94038679 (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 Apr 4, 2013 Feb 28, 2024 Oct 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000089.4:c.838G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000080.2:p.Gly280Ser missense NC_000007.14:g.94409367G>A NC_000007.13:g.94038679G>A NG_007405.1:g.19807G>A LRG_2:g.19807G>A LRG_2t1:c.838G>A LRG_2p1:p.Gly280Ser - Protein change
- G280S
- Other names
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- Canonical SPDI
- NC_000007.14:94409366:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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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COL1A2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
2037 | 2061 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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) |
criteria provided, single submitter
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Aug 18, 2011 | RCV000029613.10 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000517418.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2023 | RCV002228065.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 25, 2022 | RCV002255121.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 21, 2022 | RCV002288521.8 |
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
Help
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
Help
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
Help
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
(Nov 17, 2014)
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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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Athena Diagnostics Inc
Accession: SCV000612924.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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Osteogenesis Imperfecta
(autosomal dominant)
Affected status: unknown, yes
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052265.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 7
Observation 2:
Number of individuals with the variant: 2
Observation 3:
Tissue: Blood
Observation 4:
Tissue: Blood
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Pathogenic
(May 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Increased susceptibility to fractures
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002526716.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Comment:
_x000D_ Criteria applied: PM1_STR, PS4_MOD, PM5, PP3, PP4
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Pathogenic
(Feb 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581375.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Oct 03, 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: SCV001803818.3
First in ClinVar: Aug 21, 2021 Last updated: Nov 25, 2023 |
Comment:
Identified in multiple other unrelated patients with OI types I and IV in published literature (Roschger et al., 2008; Zhang et al., 2012; Rauch et … (more)
Identified in multiple other unrelated patients with OI types I and IV in published literature (Roschger et al., 2008; Zhang et al., 2012; Rauch et al., 2014; Maioli et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain and replaces a glycine in a canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Jovanovic et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25086671, 17078022, 30886339, 28378289, 21667357, 10807697, 31414283, 26177859, 18311573, 34007986, 35909573, 37758163) (less)
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Pathogenic
(Jul 23, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002017445.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type I
Ehlers-Danlos syndrome, classic type, 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000752610.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 280 of the COL1A2 protein (p.Gly280Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 280 of the COL1A2 protein (p.Gly280Ser). This variant is present in population databases (rs72656387, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 17078022, 21667357, 26177859, 28378289). ClinVar contains an entry for this variant (Variation ID: 35957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL1A2 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL1A2. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808325.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955056.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta. | Bardai G | Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA | 2017 | PMID: 28378289 |
Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. | Lindahl K | European journal of human genetics : EJHG | 2015 | PMID: 26177859 |
The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. | Zhang ZL | Journal of bone and mineral metabolism | 2012 | PMID: 21667357 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
Evidence that abnormal high bone mineralization in growing children with osteogenesis imperfecta is not associated with specific collagen mutations. | Roschger P | Calcified tissue international | 2008 | PMID: 18311573 |
Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. | Marini JC | Human mutation | 2007 | PMID: 17078022 |
The human type I collagen mutation database. | Dalgleish R | Nucleic acids research | 1997 | PMID: 9016532 |
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. | Bella J | Science (New York, N.Y.) | 1994 | PMID: 7695699 |
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence. | Long CG | Biochemistry | 1993 | PMID: 8218237 |
Text-mined citations for rs72656387 ...
HelpRecord last updated Mar 17, 2024
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.