rs72654802

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000088.4(COL1A1):c.3235G>A(p.Gly1079Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,425,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1079G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.71

Publications

15 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 17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_000088.4

PM2

Very rare variant in population databases, with high coverage;

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, 0.994

PP5

Variant 17-50188122-C-T is Pathogenic according to our data. Variant chr17-50188122-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17322.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.3235G>A	p.Gly1079Ser	missense_variant	Exon 44 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.3037G>A	p.Gly1013Ser	missense_variant	Exon 41 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.2965G>A	p.Gly989Ser	missense_variant	Exon 42 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.2317G>A	p.Gly773Ser	missense_variant	Exon 31 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A1	ENST00000225964.10 link	c.3235G>A	p.Gly1079Ser	missense_variant	Exon 44 of 51	1	NM_000088.4	ENSP00000225964.6	P02452
COL1A1	ENST00000486572.1 link	n.433G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
COL1A1	ENST00000511732.1 link	n.559G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1425036

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32614

American (AMR)

AF:

0.00

AC:

AN:

38890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25436

East Asian (EAS)

AF:

0.00

AC:

AN:

37816

South Asian (SAS)

AF:

0.00

AC:

AN:

82740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1092026

Other (OTH)

AF:

0.00

AC:

AN:

58930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type I

Pathogenic:4

Jul 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 29, 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 1079 of the COL1A1 protein (p.Gly1079Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (OI) type I and OI types I, III and IV (PMID: 1634225, 18311573, 21594610, 21667357, 23079818, 26177859, 27509835, 28498836, 28810924). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17322). 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 COL1A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL1A1 function (PMID: 7695699, 8218237, 18845533, 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. -

Nov 29, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Medical Sciences, Uppsala University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jun 04, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (PMID: 34007986); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as G901S; This variant is associated with the following publications: (PMID: 37270749, 35909573, 27060301, 21280025, 23079818, 27509835, 26177859, 21594610, 18218237, 18311573, 28498836, 21667357, 28810924, 25944380, 31414283, 34358384, 32166892, Tian2020[Article], 31429852, 35456387, 37859607, 17078022, 15241796, 30715774, 18845533, 34007986, 1634225, 1886404) -

Mar 30, 2020

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta type I;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP2+PS3_Moderate+PS4+PP1_Strong+PP4+PM6_Supporting -

COL1A1-related disorder

Pathogenic:1

Aug 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL1A1 c.3235G>A variant is predicted to result in the amino acid substitution p.Gly1079Ser. This variant was reported in multiple individuals with osteogenesis imperfecta (OI), or OI/Danlos Overlap syndrome (for examples: reported as p.Gly901Ser in Mottes. 1992. PubMed ID: 1634225; Moraes. 2012. PubMed ID: 23079818; de novo in Morabito. 2022. PubMed ID: 35456387). The p.Gly1079 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Marini et al. 2007. PubMed ID: 17078022).This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PhyloP100

7.7

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Vest4

0.98

MutPred

0.98

Gain of glycosylation at G1079 (P = 7e-04);

MVP

0.99

MPC

0.56

ClinPred

1.0

GERP RS

5.3

gMVP

1.0

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over