17-50194375-C-T

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.1588G>A(p.Gly530Ser) 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. G530C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.91

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:

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 1 benign, 4 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 chr17-50194375-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1420638.Status of the report is criteria_provided_single_submitter, 1 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, 0.995

PP5

Variant 17-50194375-C-T is Pathogenic according to our data. Variant chr17-50194375-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL1A1	NM_000088.4 link	c.1588G>A	p.Gly530Ser	missense_variant	Exon 23 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2 link	c.1390G>A	p.Gly464Ser	missense_variant	Exon 20 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.1588G>A	p.Gly530Ser	missense_variant	Exon 23 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.958-1682G>A		intron_variant	Intron 14 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL1A1	ENST00000225964.10 link	c.1588G>A	p.Gly530Ser	missense_variant	Exon 23 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000471344.1 link	n.532G>A		non_coding_transcript_exon_variant	Exon 7 of 8	2
COL1A1	ENST00000463440.1 link	n.-23G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000559

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type III

Pathogenic:2

Jan 15, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Oct 20, 2023

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:2

Feb 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL1A1 c.1588G>A; p.Gly530Ser variant (rs67682641), also known as Gly352Ser in traditional nomenclature, is reported in the literature in multiple individuals affected with osteogenesis imperfecta, including at least one individual in which it was found to occur de novo (Bateman 1992, Higuchi 2021, Holtz 2023, Madhuri 2021, Tuysuz 2022). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.978). This codon is located in a Gly-X-Y 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: Bateman JF et al. Characterization of three osteogenesis imperfecta collagen alpha 1(I) glycine to serine mutations demonstrating a position-dependent gradient of phenotypic severity. Biochem J. 1992 Nov 15;288 ( Pt 1)(Pt 1):131-5. PMID: 1445258. Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. PMID: 21912751. Higuchi Y et al. Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands. Mol Genet Genomic Med. 2021 Jun;9(6):e1675. PMID: 33939306. Holtz AP et al. Genetic analysis of osteogenesis imperfecta in a large Brazilian cohort. Bone. 2023 Apr;169:116683. PMID: 36709916. Madhuri V et al. Osteogenesis imperfecta: Novel genetic variants and clinical observations from a clinical exome study of 54 Indian patients. Ann Hum Genet. 2021 Jan;85(1):37-46. PMID: 32770541. Tuysuz B et al. Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1/A2 and biallelic variants. Bone. 2022 Feb;155:116293. PMID: 34902613.

Feb 27, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Also known as p.(Gly352Ser); This variant is associated with the following publications: (PMID: 27509835, 31414283, 32166892, 22589248, 7691343, 8456809, 8094076, 1445258, 17078022, 36951356, 34902613, 32770541, 34007986, 38003005, 31391747, 36709916, 37079061, 33939306)

Osteogenesis imperfecta with normal sclerae, dominant form

Pathogenic:1

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 triple helical domain of collagen type I alpha1 chain. This variant is absent from the Genome Aggregation Database (v2.1.1). Advanced training algorithm score (0.9951) found in DANN predict this variant as damaging. This specific variant has been reported in the literature (PMID: 27509835). 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 (PMID: 27509835).

Osteogenesis imperfecta type I

Pathogenic:1

Jul 30, 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 530 of the COL1A1 protein (p.Gly530Ser). 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 IV (PMID: 1445258, 7691343, 8094076, 8456809, 17078022, 22589248, 27509835). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17324). 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%. 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.95

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Vest4

0.99

ClinPred

1.0

GERP RS

5.1

gMVP

1.0

Mutation Taster

=6/94

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

Other links and lift over