VCV000641929.9 - ClinVar

NM_000089.4(COL1A2):c.2098G>T (p.Gly700Cys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (2)

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000089.4(COL1A2):c.2098G>T (p.Gly700Cys)

Variation ID: 641929 Accession: VCV000641929.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.3 7: 94420251 (GRCh38) [ NCBI UCSC ] 7: 94049563 (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	Aug 14, 2019	Feb 23, 2026	Apr 28, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000089.4:c.2098G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000080.2:p.Gly700Cys	missense
NC_000007.14:g.94420251G>T
NC_000007.13:g.94049563G>T
NG_007405.1:g.30691G>T
LRG_2:g.30691G>T
LRG_2t1:c.2098G>T	LRG_2p1:p.Gly700Cys

... more HGVS ... less HGVS

Protein change

G700C

Other names

Canonical SPDI

NC_000007.14:94420250:G:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA162935392 dbSNP: rs72658160 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	2834	2860

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.
Ehlers-Danlos syndrome, classic type, 1 Osteogenesis imperfecta type I	Pathogenic (1)	criteria provided, single submitter	Apr 28, 2025	RCV002234258.14
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 24, 2022	RCV003223677.8

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.	Expand all rows Collapse all rows 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 (Oct 24, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV003919648.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: show 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); 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: 34007986, 35225118, 25829218, 31485550, 19594296, 30579604) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Apr 28, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	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.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000934738.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 23, 2026	Publications: PubMed (6) PubMed: 17078022‚ 19344236‚ 19594296‚ 7695699‚ 8218237‚ 9016532 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 700 of the COL1A2 protein (p.Gly700Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 19594296). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly610Cys. ClinVar contains an entry for this variant (Variation ID: 641929). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL1A2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL1A2 function (PMID: 19594296). 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

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 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); 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: 34007986, 35225118, 25829218, 31485550, 19594296, 30579604)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 700 of the COL1A2 protein (p.Gly700Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 19594296). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly610Cys. ClinVar contains an entry for this variant (Variation ID: 641929). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL1A2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL1A2 function (PMID: 19594296). 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model.	Daley E	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2010	PMID: 19594296
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
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 rs72658160 ...

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 Aug 08, 2026