VCV000425643.40 - ClinVar

NM_000089.4(COL1A2):c.1009G>A (p.Gly337Ser)

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.

(12)

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.1009G>A (p.Gly337Ser)

Variation ID: 425643 Accession: VCV000425643.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.3 7: 94409795 (GRCh38) [ NCBI UCSC ] 7: 94039107 (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	Jun 10, 2017	Oct 20, 2024	Jan 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000089.4:c.1009G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000080.2:p.Gly337Ser	missense
NC_000007.14:g.94409795G>A
NC_000007.13:g.94039107G>A
NG_007405.1:g.20235G>A
LRG_2:g.20235G>A
LRG_2t1:c.1009G>A	LRG_2p1:p.Gly337Ser

... more HGVS ... less HGVS

Protein change

G337S

Other names

Canonical SPDI

NC_000007.14:94409794: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: CA162920380 dbSNP: rs67865220 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.
Osteogenesis imperfecta type I	Pathogenic (1)	no assertion criteria provided	-	RCV000490720.10
Osteogenesis imperfecta type III	Pathogenic (1)	no assertion criteria provided	Jan 6, 2020	RCV000993573.10
Ehlers-Danlos syndrome, classic type	Pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000987924.10
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2023	RCV001553203.28
Osteogenesis imperfecta type III Osteogenesis imperfecta with normal sclerae, dominant form	Pathogenic (1)	criteria provided, single submitter	Mar 9, 2020	RCV001250519.10
Osteogenesis imperfecta	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 30, 2023	RCV002279258.12
Ehlers-Danlos syndrome, classic type, 1 Osteogenesis imperfecta type I	Pathogenic (1)	criteria provided, single submitter	Dec 31, 2023	RCV002230964.13
COL1A2-related disorder	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2023	RCV004535542.1
Ehlers-Danlos syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 24, 2024	RCV003987562.1
Ehlers-danlos syndrome, arthrochalasia type, 2	no classifications from unflagged records (1)	no classifications from unflagged records	May 16, 2024	RCV003989538.3

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 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 (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Ehlers-Danlos syndrome, classic type, 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137418.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Mar 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta type III Osteogenesis imperfecta with normal sclerae, dominant form Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001425314.1 First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020	Publications: PubMed (6) PubMed: 17078022‚ 22206639‚ 25944380‚ 7695699‚ 8829649‚ 9016532
Pathogenic (Apr 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002564760.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Pathogenic (Dec 08, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001774027.2 First in ClinVar: Aug 07, 2021 Last updated: Dec 24, 2022	Comment: Glycine substitution within the Gly-X-Y repeat in the collagenous domain of COL1A2; In silico analysis supports that this missense variant has a deleterious effect on … (more) Glycine substitution within the Gly-X-Y repeat in the collagenous domain of COL1A2; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10942108, 24501682, 32333414, 34367232, 22206639, 27510842, 26138843, 27748872, 16882741, 25944380, 8829649, 21667357, 28810924, 27519266, 28116328, 30715774, 17078022, 9016532, 28498836, 30886339, 32081708, 32166892, 24077912) (less)
Pathogenic (Dec 31, 2023)	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: SCV000627288.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (16) PubMed: 8829649‚ 21667357‚ 22206639‚ 24501682‚ 25944380‚ 26138843‚ 27510842‚ 27519266‚ 27748872‚ 28498836‚ 28810924‚ 7695699‚ 8218237‚ 19344236‚ 9016532‚ 17078022 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 337 of the COL1A2 protein (p.Gly337Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 337 of the COL1A2 protein (p.Gly337Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta types I, III, and IV (PMID: 8829649, 21667357, 22206639, 24501682, 25944380, 26138843, 27510842, 27519266, 27748872, 28498836, 28810924). ClinVar contains an entry for this variant (Variation ID: 425643). 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)
Pathogenic (Feb 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002497533.18 First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 4
Pathogenic (Nov 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	COL1A2-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004244672.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: PS4, PM1, PM2, PM5, PP3
Pathogenic (Jan 24, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Ehlers-Danlos syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004803736.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (3) PubMed: 27519266‚ 28498836‚ 4795106 Comment: Variant summary: COL1A2 c.1009G>A (p.Gly337Ser) results in a non-conservative amino acid change in the Gly-X-Y repeat region of the encoded protein sequence. Five of five … (more) Variant summary: COL1A2 c.1009G>A (p.Gly337Ser) results in a non-conservative amino acid change in the Gly-X-Y repeat region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250384 control chromosomes (gnomAD). c.1009G>A has been reported in the literature in individuals affected with Osteogenesis imperfecta (examples: Lindahl_2015, Andersson_2016, Ho Duy_2016). At-least one of these cases was reported as a de novo occurrence (Lindahl_2015). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28498836, PMC4795106, 27519266). ClinVar contains an entry for this variant (Variation ID: 425643). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Mar 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812414.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (3) PubMed: 8218237‚ 8829649‚ 33070251 Comment: This sequence change in COL1A2 is predicted to replace glycine with serine at codon 337, p.(Gly337Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), … (more) This sequence change in COL1A2 is predicted to replace glycine with serine at codon 337, p.(Gly337Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in glycine-altering in a Gly-X-Y collagen triple-helical repeat (PMID: 8218237). There is a small physicochemical difference between glycine and serine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in many unrelated individuals with a clinical diagnosis of osteogenesis imperfecta (PMID: 8829649, 33070251). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4_VeryStrong, PM1, PM2_Supporting, PP3. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	OI type I Affected status: yes Allele origin: maternal	Department of Medical Sciences, Uppsala University Additional submitter: Department of Dental Medicine, Karolinska Institutet Accession: SCV000574645.1 First in ClinVar: Jun 10, 2017 Last updated: Jun 10, 2017	Publications: PubMed (1) PubMed: 25944380 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: clinical testing	Osteogenesis imperfecta type III (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Center of Excellence for Medical Genomics, Chulalongkorn University Accession: SCV001134943.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Sex: female
Uncertain significance (Mar 26, 2024)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Ehlers-danlos syndrome, arthrochalasia type, 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807330.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
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Comment:

Glycine substitution within the Gly-X-Y repeat in the collagenous domain of COL1A2; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10942108, 24501682, 32333414, 34367232, 22206639, 27510842, 26138843, 27748872, 16882741, 25944380, 8829649, 21667357, 28810924, 27519266, 28116328, 30715774, 17078022, 9016532, 28498836, 30886339, 32081708, 32166892, 24077912)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 337 of the COL1A2 protein (p.Gly337Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta types I, III, and IV (PMID: 8829649, 21667357, 22206639, 24501682, 25944380, 26138843, 27510842, 27519266, 27748872, 28498836, 28810924). ClinVar contains an entry for this variant (Variation ID: 425643). 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.

Comment:

Variant summary: COL1A2 c.1009G>A (p.Gly337Ser) results in a non-conservative amino acid change in the Gly-X-Y repeat region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250384 control chromosomes (gnomAD). c.1009G>A has been reported in the literature in individuals affected with Osteogenesis imperfecta (examples: Lindahl_2015, Andersson_2016, Ho Duy_2016). At-least one of these cases was reported as a de novo occurrence (Lindahl_2015). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28498836, PMC4795106, 27519266). ClinVar contains an entry for this variant (Variation ID: 425643). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change in COL1A2 is predicted to replace glycine with serine at codon 337, p.(Gly337Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in glycine-altering in a Gly-X-Y collagen triple-helical repeat (PMID: 8218237). There is a small physicochemical difference between glycine and serine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in many unrelated individuals with a clinical diagnosis of osteogenesis imperfecta (PMID: 8829649, 33070251). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4_VeryStrong, PM1, PM2_Supporting, PP3.

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
Clinical and genetic analysis in 185 Chinese probands of osteogenesis imperfecta.	Xi L	Journal of bone and mineral metabolism	2021	PMID: 33070251
Mutational analysis of COL1A1 and COL1A2 genes among Estonian osteogenesis imperfecta patients.	Zhytnik L	Human genomics	2017	PMID: 28810924
Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta - A retrospective cohort study.	Andersson K	PloS one	2017	PMID: 28498836
Tooth agenesis in osteogenesis imperfecta related to mutations in the collagen type I genes.	Malmgren B	Oral diseases	2017	PMID: 27510842
Clinical characteristics and the identification of novel mutations of COL1A1 and COL1A2 in 61 Chinese patients with osteogenesis imperfecta.	Zhang H	Molecular medicine reports	2016	PMID: 27748872
Mutation analysis of the COL1A1 and COL1A2 genes in Vietnamese patients with osteogenesis imperfecta.	Ho Duy B	Human genomics	2016	PMID: 27519266
Genetics of Osteoporosis in Children.	van Dijk FS	Endocrine development	2015	PMID: 26138843
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
Whole exome sequencing is an efficient, sensitive and specific method of mutation detection in osteogenesis imperfecta and Marfan syndrome.	McInerney-Leo AM	BoneKEy reports	2013	PMID: 24501682
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
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
The effect of prolonged administration of hydrochlorothiazide on the renal lithium clearance and the urine flow of ordinary rats and rats with diabetes insipidus.	Thomsen K	Pharmakopsychiatrie, Neuro-Psychopharmakologie	1973	PMID: 4795106
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Text-mined citations for rs67865220 ...

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.1009G>A (p.Gly337Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs67865220 ...