rs72653178

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000088.4(COL1A1):c.3118G>A(p.Gly1040Ser) 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. G1040A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.82

Publications

14 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 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 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 chr17-50188618-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1806458.Status of the report is no_assertion_criteria_provided, 0 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, 0.992

PP5

Variant 17-50188619-C-T is Pathogenic according to our data. Variant chr17-50188619-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.3118G>A	p.Gly1040Ser	missense_variant	Exon 43 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.2920G>A	p.Gly974Ser	missense_variant	Exon 40 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.2848G>A	p.Gly950Ser	missense_variant	Exon 41 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.2200G>A	p.Gly734Ser	missense_variant	Exon 30 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A1	ENST00000225964.10 link	c.3118G>A	p.Gly1040Ser	missense_variant	Exon 43 of 51	1	NM_000088.4	ENSP00000225964.6	P02452
COL1A1	ENST00000511732.1 link	n.62G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
COL1A1	ENST00000486572.1 link	n.-65G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type III

Pathogenic:4

Jun 18, 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 serine residue in the alpha 2 chain of collagen type I. This variant is absent from gnomAD (v2.1.1) indicating it is very rare. This variant has been reported in the literature (PMID: 27509835). We have observed this variant in 7 individuals with a diagnosis of osteogenesis imperfecta. Computational tools (Revel 0.98) suggest that the change is detrimental to protein function. 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. -

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017330). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25944380). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Department of Medical Sciences, Uppsala University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:4

Mar 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, and this is an established mechanism of disease (HGMD); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9101304, 32234057, 8125479, 27509835, 26177859, 29499418, 18670065, 18798308, 7789952, 30886339, 31715670, 31994750, 32436246, 32123938, 33939306) -

Apr 29, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL1A1 c.3118G>A; p.Gly1040Ser variant (rs72653178), also known as p.Gly862Ser, is reported in the literature in several individuals affected with osteogenesis imperfecta (Bardai 2016, Lindahl 2015, Maioli 2019, Mrosk 2018, Obafemi 2008). This variant is reported in ClinVar (Variation ID: 17330), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 1040 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This codon is located in a triple helix repeat domain, and glycine substitutions are the most frequent pathogenic alterations in this region (Ben Amor 2011). Based on available information, this variant is considered to be pathogenic. References: Bardai G et al. DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int. 2016 Dec;27(12):3607-3613. Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Lindahl K et al. Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. Eur J Hum Genet. 2015 Aug;23(8):1112. Maioli M et al. Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients. Eur J Hum Genet. 2019 Jul;27(7):1090-1100. Mrosk J et al. Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone. 2018 May;110:368-377. Obafemi AA et al. Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation. Am J Med Genet A. 2008 Nov 1;146A(21):2725-32. -

Jan 10, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2012

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta type I

Pathogenic:2

Jun 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1040 of the COL1A1 protein (p.Gly1040Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta type III and osteogenesis imperfecta type III or IV (PMID: 7789952, 18670065, 18798308, 26177859, 27509835). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17330). 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%. Experimental studies have shown that this missense change affects COL1A1 function (PMID: 7695699, 8218237, 9016532, 17078022, 18670065, 19344236). 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. -

Jul 02, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with osteogenesis imperfecta. Haploinsufficiency and missense variants that disrupt collagen structure are both known to be pathogenic (PMID: 12362985). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif. Variants that disrupt the glycine of the Gly-X-Y motif are known to product structural defects in the collagen molecule (PMID: 12362985). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many individuals with osteogenesis imperfecta in ClinVar and the literature (PMID: 17078022, 26177859, 27509835). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Osteogenesis imperfecta, perinatal lethal

Pathogenic:1

Feb 25, 2022

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

A heterozygous non-synonymous variation NM_000088.4:c.3118G>A (p.Ala1040Ser) in exon 43 of COL1A1 gene was detected in fetus. The above variant was not detected in both the parents of proband, who are asymptomatic. Sanger sequencing in proband has validated the variant. There by showing the de novo nature of this variant. c.3118G>A is a missense 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, and this is an established mechanism of disease (HGMD); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. This variant has been classified as pathogenic according to the ACMG guidelines (PP5, PM1, PM2, PP2, PP3) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PhyloP100

7.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Vest4

1.0

MutPred

0.97

Gain of glycosylation at G1040 (P = 0.0031);

MVP

0.99

MPC

0.56

ClinPred

1.0

GERP RS

4.5

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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