VCV000526895.15 - ClinVar

NM_000089.4(COL1A2):c.1378G>A (p.Gly460Ser)

Germline

Classification

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.

(5)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000089.4(COL1A2):c.1378G>A (p.Gly460Ser)

Variation ID: 526895 Accession: VCV000526895.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.3 7: 94412095 (GRCh38) [ NCBI UCSC ] 7: 94041407 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	May 28, 2018	Feb 28, 2024	Sep 10, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000089.4:c.1378G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000080.2:p.Gly460Ser	missense
NC_000007.14:g.94412095G>A
NC_000007.13:g.94041407G>A
NG_007405.1:g.22535G>A
LRG_2:g.22535G>A
LRG_2t1:c.1378G>A	LRG_2p1:p.Gly460Ser

... more HGVS ... less HGVS

Protein change

G460S

Other names

Canonical SPDI

NC_000007.14:94412094:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA162924592 dbSNP: rs72658118 VarSome

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help 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.
COL1A2		No evidence available	No evidence available	GRCh38 GRCh37	2109	2132

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 Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 11, 2022	RCV001597190.15
Ehlers-Danlos syndrome, classic type, 1 Osteogenesis imperfecta type I	Pathogenic (1)	criteria provided, single submitter	Sep 10, 2022	RCV002234410.14
Osteogenesis imperfecta, perinatal lethal	Pathogenic (1)	criteria provided, single submitter	-	RCV003313968.8

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.
Pathogenic (Mar 13, 2020)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832515.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
Pathogenic (Apr 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002499975.2 First in ClinVar: Apr 23, 2022 Last updated: Mar 04, 2023	Comment: Variant occurs in the triple helical domain and replaces the Glycine in the canonical Gly-X-Y repeat. Missense substitution of a canonical Glycine residue is expected … (more) Variant occurs in the triple helical domain and replaces the Glycine in the canonical Gly-X-Y repeat. Missense substitution of a canonical Glycine residue is expected to disrupt normal protein folding and function, which is an established mechanism of disease.; Not observed in large population cohorts (gnomAD); 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: 22589248, 29620724, 19344236, 15241796, 22206639, 7695699, 8218237, 9016532, 17078022, 26627451, 27519266, 32335877, 34007986, 30266093, 32123938, 33939306, 33942288, 8829649) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta, perinatal lethal Affected status: yes Allele origin: unknown	3billion Accession: SCV004013695.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 8829649 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: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000526895 / PMID: 8829649 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Bowing of the legs (present) , Femoral bowing (present) , Tibial bowing (present) , Limb undergrowth (present) , Single transverse palmar crease (present) , Cryptorchidism … (more) Bowing of the legs (present) , Femoral bowing (present) , Tibial bowing (present) , Limb undergrowth (present) , Single transverse palmar crease (present) , Cryptorchidism (present) , Blue sclerae (present) , Relative macrocephaly (present) , Midface retrusion (present) (less)
Pathogenic (May 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017434.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Sep 10, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000752615.4 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (10) PubMed: 7695699‚ 8218237‚ 19344236‚ 9016532‚ 17078022‚ 8829649‚ 22206639‚ 22589248‚ 26627451‚ 27519266 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL1A2. Glycine residues within the Gly-Xaa-Yaa repeats … (more) For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 526895). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 8829649, 22206639, 22589248, 26627451, 27519266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 460 of the COL1A2 protein (p.Gly460Ser). (less)

Comment:

Variant occurs in the triple helical domain and replaces the Glycine in the canonical Gly-X-Y repeat. Missense substitution of a canonical Glycine residue is expected to disrupt normal protein folding and function, which is an established mechanism of disease.; Not observed in large population cohorts (gnomAD); 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: 22589248, 29620724, 19344236, 15241796, 22206639, 7695699, 8218237, 9016532, 17078022, 26627451, 27519266, 32335877, 34007986, 30266093, 32123938, 33939306, 33942288, 8829649)

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 the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000526895 / PMID: 8829649 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 526895). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 8829649, 22206639, 22589248, 26627451, 27519266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 460 of the COL1A2 protein (p.Gly460Ser).

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation analysis of the COL1A1 and COL1A2 genes in Vietnamese patients with osteogenesis imperfecta.	Ho Duy B	Human genomics	2016	PMID: 27519266
Genotype and phenotype analysis of Taiwanese patients with osteogenesis imperfecta.	Lin HY	Orphanet journal of rare diseases	2015	PMID: 26627451
Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms.	Thiele F	Human molecular genetics	2012	PMID: 22589248
Osteogenesis Imperfecta: the audiological phenotype lacks correlation with the genotype.	Swinnen FK	Orphanet journal of rare diseases	2011	PMID: 22206639
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
The human type I collagen mutation database.	Dalgleish R	Nucleic acids research	1997	PMID: 9016532
Direct sequencing of PCR products derived from cDNAs for the pro alpha 1 and pro alpha 2 chains of type I procollagen as a screening method to detect mutations in patients with osteogenesis imperfecta.	Zhuang J	Human mutation	1996	PMID: 8829649
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 rs72658118 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000089.4(COL1A2):c.1378G>A (p.Gly460Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72658118 ...