17-50194032-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000088.4(COL1A1):c.1678G>A(p.Gly560Ser) 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. G560C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.69

Publications

17 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-50194032-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 526860.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, 0.993

PP5

Variant 17-50194032-C-T is Pathogenic according to our data. Variant chr17-50194032-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 265433.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.1678G>A	p.Gly560Ser	missense_variant	Exon 25 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.1480G>A	p.Gly494Ser	missense_variant	Exon 22 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.1678G>A	p.Gly560Ser	missense_variant	Exon 25 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.958-1339G>A		intron_variant	Intron 14 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A1	ENST00000225964.10 link	c.1678G>A	p.Gly560Ser	missense_variant	Exon 25 of 51	1	NM_000088.4	ENSP00000225964.6	P02452
COL1A1	ENST00000463440.1 link	n.68G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
COL1A1	ENST00000471344.1 link	n.710G>A		non_coding_transcript_exon_variant	Exon 8 of 8	2
COL1A1	ENST00000476387.1 link	n.27G>A		non_coding_transcript_exon_variant	Exon 1 of 9	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type I

Pathogenic:7

Jul 16, 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 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. This variant is absent from the Genome Aggregation Database (v2.1.1). This variant has been reported in the literature (PMID: 27509835). We have observed this variant in our laboratory variant database in >10 individuals diagnosed with osteogenesis imperfecta. -

Feb 23, 2023

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: 0.99; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265433). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15741671, 17078022, 19751715, 22753364, 24668929, 27510842, 7691343). Different missense changes at the same codon (p.Gly560Arg, p.Gly560Cys) have been reported to be associated with COL1A1 related disorder (ClinVar ID: VCV000526860 / PMID: 2238087, 8799376). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 20, 2017

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Suma Genomics

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

- -

Dec 23, 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 560 of the COL1A1 protein (p.Gly560Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta types III and IV (PMID: 7691343, 15741671, 17078022, 19751715, 22753364, 24668929, 27510842). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly382Ser. ClinVar contains an entry for this variant (Variation ID: 265433). 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%. 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. -

Aug 24, 2022

Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Jun 27, 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); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G382S) using alternate nomenclature; This variant is associated with the following publications: (PMID: 25944380, 36307859, 36709916, 37270749, 37880672, 34627339, 7691343, 17078022, 15741671, 22753364, 26432670, 26177859, 27510842, 30715774, 30692697, 30886339, 31299979, 32981126, 33939306, 28528406, 36140746, 34358384, 24668929, 34007986) -

Nov 30, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 02, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta

Pathogenic:2

Nov 18, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Pathogenic:1

Nov 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COL1A1-related disorder

Pathogenic:1

Jun 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The COL1A1 c.1678G>A variant is predicted to result in the amino acid substitution p.Gly560Ser. This variant, also known as p.Gly382Ser using legacy nomenclature, has been reported in patients with various types of osteogenesis imperfecta (OI): type I (Patient 15 in Malmgren et al. 2016. PubMed ID: 27510842); type II (Patient AN_006035 in Additional file 1 in Maioli et al. 2019. PubMed ID: 30886339); type III (P18 in Kanno et al. 2017. PubMed ID: 28528406); type IV (Patient # 74 in Reis et al. 2005. PubMed ID: 15741671; Patient AN_000044 in Gentile et al. 2012. PubMed ID: 22753364); type I/IV (Patient 4 in Stephen et al. 2014. PubMed ID: 24668929). This variant has been documented as causing "moderate to severe" OI (Higuchi et al. 2021. PubMed ID: 33939306). This variant is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Residues 179-1192, https://www.uniprot.org/; Legacy nomenclature in Marini et al. 2007. PubMed ID: 17078022; Symoens et al. 2014. PubMed ID: 25146735). This variant has not been reported in a large population database, indicating this variant is rare. Based on this evidence, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.97

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PhyloP100

7.7

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.99

MutPred

0.99

Gain of phosphorylation at G560 (P = 0.0099);

MVP

0.99

MPC

0.56

ClinPred

1.0

GERP RS

4.4

gMVP

1.0

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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