ClinVar Genomic variation as it relates to human health
NM_000088.4(COL1A1):c.1678G>A (p.Gly560Ser)
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_000088.4(COL1A1):c.1678G>A (p.Gly560Ser)
Variation ID: 265433 Accession: VCV000265433.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.33 17: 48271393 (GRCh37) [ NCBI UCSC ] 17: 50194032 (GRCh38) [ 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 Oct 10, 2016 Feb 20, 2024 Dec 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000088.4:c.1678G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000079.2:p.Gly560Ser missense NC_000017.11:g.50194032C>T NC_000017.10:g.48271393C>T NG_007400.1:g.12608G>A LRG_1:g.12608G>A LRG_1t1:c.1678G>A LRG_1p1:p.Gly560Ser - Protein change
- G560S
- Other names
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- Canonical SPDI
- NC_000017.11:50194031: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.
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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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COL1A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2681 | 2877 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jul 18, 2022 | RCV000255844.10 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000293333.14 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 13, 2020 | RCV000722158.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2019 | RCV002278251.3 |
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
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
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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
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
(Jul 18, 2022)
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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: SCV000322325.10
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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 in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G382S) using alternate nomenclature; This variant is associated with the following publications: (PMID: 25944380, 7691343, 17078022, 15741671, 22753364, 26432670, 26177859, 27510842, 30715774, 30692697, 30886339, 31299979, 32981126, 33939306, 28528406, 24668929, 34007986) (less)
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Pathogenic
(Sep 02, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000334706.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type I
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000627182.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 560 of the COL1A1 protein (p.Gly560Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 560 of the COL1A1 protein (p.Gly560Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta types III and IV (PMID: 7691343, 15741671, 17078022, 19751715, 22753364, 24668929, 27510842). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly382Ser. ClinVar contains an entry for this variant (Variation ID: 265433). 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 COL1A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL1A1. 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 COL1A1, 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
(Nov 30, 2019)
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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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Blueprint Genetics
Accession: SCV001832315.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type I
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Suma Genomics
Accession: SCV001847713.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
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Pathogenic
(Jan 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002565130.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Pathogenic
(Nov 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002565473.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type I
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841783.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265433). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15741671, 17078022, 19751715, 22753364, 24668929, 27510842, 7691343). Different missense changes at the same codon (p.Gly560Arg, p.Gly560Cys) have been reported to be associated with COL1A1 related disorder (ClinVar ID: VCV000526860 / PMID: 2238087, 8799376). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Femoral bowing (present) , Blue sclerae (present) , Dentinogenesis imperfecta (present) , Generalized hypotonia (present) , Global developmental delay (present) , Wormian bones (present) , … (more)
Femoral bowing (present) , Blue sclerae (present) , Dentinogenesis imperfecta (present) , Generalized hypotonia (present) , Global developmental delay (present) , Wormian bones (present) , Frontal bossing (present) (less)
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Pathogenic
(Aug 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type I
Affected status: yes
Allele origin:
de novo
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Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province
Accession: SCV003915609.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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OI type I
Affected status: yes
Allele origin:
maternal
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Department of Medical Sciences, Uppsala University
Additional submitter:
Department of Dental Medicine, Karolinska Institutet
Accession: SCV000574595.1
First in ClinVar: Jun 09, 2017 Last updated: Jun 09, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
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Pathogenic
(Apr 20, 2017)
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no assertion criteria provided
Method: clinical testing
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Osteogenesis imperfecta type I
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000599800.1
First in ClinVar: Jun 09, 2017 Last updated: Jun 09, 2017 |
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Pathogenic
(Nov 18, 2018)
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no assertion criteria provided
Method: clinical testing
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osteogenesis imperfecta
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000854595.1
First in ClinVar: Dec 07, 2018 Last updated: Dec 07, 2018 |
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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 analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands. | Higuchi Y | Molecular genetics & genomic medicine | 2021 | PMID: 33939306 |
A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review. | Dempsey E | BJOG : an international journal of obstetrics and gynaecology | 2021 | PMID: 32981126 |
Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases. | Liu Y | Diagnostic pathology | 2019 | PMID: 31299979 |
Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients. | Maioli M | European journal of human genetics : EJHG | 2019 | PMID: 30886339 |
Genotypic and phenotypic characterization of Chinese patients with osteogenesis imperfecta. | Li L | Human mutation | 2019 | PMID: 30715774 |
Tooth agenesis in osteogenesis imperfecta related to mutations in the collagen type I genes. | Malmgren B | Oral diseases | 2017 | PMID: 27510842 |
Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. | Lindahl K | European journal of human genetics : EJHG | 2015 | PMID: 25944380 |
Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta. | Stephen J | American journal of medical genetics. Part A | 2014 | PMID: 24668929 |
Validation of a quantitative PCR-high-resolution melting protocol for simultaneous screening of COL1A1 and COL1A2 point mutations and large rearrangements: application for diagnosis of osteogenesis imperfecta. | Gentile FV | Human mutation | 2012 | PMID: 22753364 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
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 |
Molecular findings in Brazilian patients with osteogenesis imperfecta. | Reis FC | Journal of applied genetics | 2005 | PMID: 15741671 |
The human type I collagen mutation database. | Dalgleish R | Nucleic acids research | 1997 | PMID: 9016532 |
Intrafamilial variable expressivity of osteogenesis imperfecta due to mosaicism for a lethal G382R substitution in the COL1A1 gene. | Cohen-Solal L | Molecular and cellular probes | 1996 | PMID: 8799376 |
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 |
An RT-PCR-SSCP screening strategy for detection of mutations in the gene encoding the alpha 1 chain of type I collagen: application to four patients with osteogenesis imperfecta. | Mackay K | Human molecular genetics | 1993 | PMID: 7691343 |
Brittle bones--fragile molecules: disorders of collagen gene structure and expression. | Byers PH | Trends in genetics : TIG | 1990 | PMID: 2238087 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL1A1 | - | - | - | - |
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Text-mined citations for rs67507747 ...
HelpRecord last updated Feb 28, 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.