rs67368147

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000088.4(COL1A1):c.2110G>T(p.Gly704Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G704S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.87

Publications

9 publications found

Variant links:

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A1 Gene-Disease associations (from GenCC):

Caffey disease
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome, arthrochalasia type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
osteogenesis imperfecta type 1
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
osteogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
osteogenesis imperfecta type 3
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
osteogenesis imperfecta type 4
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
Ehlers-Danlos syndrome, classic type, 1
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Ehlers-Danlos syndrome, classic type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ehlers-Danlos/osteogenesis imperfecta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
high bone mass osteogenesis imperfecta
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL1A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000088.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-50191805-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 811940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to high bone mass osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Caffey disease, osteogenesis imperfecta type 4, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos/osteogenesis imperfecta syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 17-50191805-C-A is Pathogenic according to our data. Variant chr17-50191805-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17288.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.2110G>T	p.Gly704Cys	missense_variant	Exon 31 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.1912G>T	p.Gly638Cys	missense_variant	Exon 28 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.2110G>T	p.Gly704Cys	missense_variant	Exon 31 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.1192G>T	p.Gly398Cys	missense_variant	Exon 18 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A1	ENST00000225964.10 link	c.2110G>T	p.Gly704Cys	missense_variant	Exon 31 of 51	1	NM_000088.4	ENSP00000225964.6	P02452
COL1A1	ENST00000476387.1 link	n.459G>T		non_coding_transcript_exon_variant	Exon 7 of 9	2
COL1A1	ENST00000504289.1 link	n.*61G>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1438718

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713518

African (AFR)

AF:

0.00

AC:

AN:

33154

American (AMR)

AF:

0.00

AC:

AN:

41578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25546

East Asian (EAS)

AF:

0.00

AC:

AN:

38914

South Asian (SAS)

AF:

0.00

AC:

AN:

83044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099664

Other (OTH)

AF:

0.00

AC:

AN:

59464

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type III

Pathogenic:2

Oct 01, 1989

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 23, 2025

Clinical Biomedical Laboratory, Shriners Hospital For Children - Canada

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is predicted to substitute a glycine residue by a cysteine residue in the triple-helical domain of the alpha 1 chain of collagen type I. Glycine substitutions in the triple helical domain of collagen type I cause disruption in the formation of the triple helix in the collagen molecule and are a typical cause of osteogenesis imperfecta. In the Genome Aggregation Database (gnomAD v2.1.1) this variant is not present. The variant is predicted to be deleterious to protein function (Revel 1.00). This variant has been reported in the literature (e.g., PMID 28498836). We have previouly observed this variant in the Shriners Hospital for Children variant database in one individual with osteogenesis imperfecta type III. -

Osteogenesis imperfecta with normal sclerae, dominant form

Pathogenic:1

Department of Medical Sciences, Uppsala University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.99

PhyloP100

7.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

1.0

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.98

MutPred

0.99

Loss of relative solvent accessibility (P = 0.0676);

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

5.3

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over