17-50188908-G-A

Variant names:

• chr17-50188908-G-A
• rs72653170
• NM_000088.4:c.3040C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 15P and 4B. PM1 PP2 PP3_Strong PP5_Very_Strong BS2

The NM_000088.4(COL1A1):​c.3040C>T​(p.Arg1014Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,451,640 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1014H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.93
• Publications: 22 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 4 uncertain in NM_000088.4
• 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, 0.941
• PP5: Variant 17-50188908-G-A is Pathogenic according to our data. Variant chr17-50188908-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.3040C>T	p.Arg1014Cys	missense	Exon 41 of 51	NP_000079.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.3040C>T	p.Arg1014Cys	missense	Exon 41 of 51	ENSP00000225964.6
	COL1A1	ENST00000511732.1	TSL:2	n.-124C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250334 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000551 AC: 8 AN: 1451640 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 722746

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000635 AC: 7 AN: 1102830

Other (OTH) AF: 0.00 AC: 0 AN: 60068

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000663 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile cortical hyperostosis Pathogenic:3 Other:1

Jul 15, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 26, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 15864348). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.14 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017347 /PMID: 15864348). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 18704262, 21249479, 21567126, 24390061). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 21567126, 24390061). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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 changes an arginine residue in the collagen type I alpha 1 chain to a cysteine residue. The variant is very rare in the gnomAD database and is predicted to be damaging to protein function (Revel 0.93. We have observed this variant in our in-house molecular diagnosis laboratory in several families with Caffey’s disease. The variant is a typical cause of Caffey’s disease and has been published in several reports (e.g., PMID 15864348).

not provided Pathogenic:2

Apr 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Skin biopsy from an affected adult with this variant demonstrated less densely packed collagen fibrils of variable shape and size surrounded by granular material, while analysis of collagen fibrils in cultured skin fibroblasts indicated increased disulfide crosslinking (Gensure et al., 2005); 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; Located in the Gly-X-Y triple helical region of the pro-alpha1(I) chain encoded by the COL1A1 gene, where triplet glycine substitutions are the most common cause of osteogenesis imperfecta (OI). The effect of missense substitution at the X and Y positions are more difficult to predict; however, multiple variants that result in introduction of a Cys residue in pro-alpha1(I) have been reported to be pathogenic (Dalgleish, 1998); This variant is associated with the following publications: (PMID: 21249479, 22855962, 15864348, 18553566, 18704262, 17309652, 21567126, 24390061)

May 21, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL1A1 c.3040C>T; p.Arg1014Cys variant (rs72653170) is reported in the literature in numerous individuals and families affected with infantile cortical hyperostosis, also called Caffey disease (Cho 2008, Gensure 2005, Kitaoka 2014, Suphapeetiporn 2007). This variant has been observed to segregate with disease in multiple families, although it exhibits incomplete penetrance (Gensure 2005, Kitaoka 2014, Suphapeetiporn 2007). In one family, the variant was found in two affected identical twins but was absent from both parents, suggesting a de novo origin (Gensure 2005). This variant is found on only two chromosomes in the Genome Aggregation Database (2/250334 alleles), indicating it is not a common polymorphism. The arginine at codon 1014 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Cho TJ et al. The c.3040C > T mutation in COL1A1 is recurrent in Korean patients with infantile cortical hyperostosis (Caffey disease). J Hum Genet. 2008;53(10):947. Gensure RC et al. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest. 2005 May;115(5):1250-7. Kitaoka T et al. Two Japanese familial cases of Caffey disease with and without the common COL1A1 mutation and normal bone density, and review of the literature. Eur J Pediatr. 2014 Jun;173(6):799-804. Suphapeetiporn K et al. Expanding the phenotypic spectrum of Caffey disease. Clin Genet. 2007 Mar;71(3):280-4.

Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029458:Postmenopausal osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4551623:Ehlers-Danlos syndrome, arthrochalasia type Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Osteogenesis imperfecta type I Pathogenic:1

Sep 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1014 of the COL1A1 protein (p.Arg1014Cys). This variant is present in population databases (rs72653170, gnomAD 0.006%). This missense change has been observed in individual(s) with Caffey disease (PMID: 15864348, 17309652, 18553566, 18704262, 21249479, 21567126, 24390061). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg836Cys. ClinVar contains an entry for this variant (Variation ID: 17347). 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: 15864348). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		9.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.022	D
Vest4		0.92
MutPred		0.70		Loss of methylation at R1014 (P = 0.0118)
MVP		0.99
MPC		0.77
ClinPred		0.98	D
GERP RS		4.0
gMVP		0.89
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs72653170; hg19: chr17-48266269; COSMIC: COSV104388046; COSMIC: COSV104388046;