dbSNP rs72653173: COL1A1:p.Arg1026* (chr17-50188765-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000088.4(COL1A1):c.3076C>T(p.Arg1026*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 4.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-50188765-G-A is Pathogenic according to our data. Variant chr17-50188765-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188765-G-A is described in Lovd as [Pathogenic]. Variant chr17-50188765-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.3076C>T	p.Arg1026*	stop_gained	Exon 42 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.2878C>T	p.Arg960*	stop_gained	Exon 39 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.2806C>T	p.Arg936*	stop_gained	Exon 40 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.2158C>T	p.Arg720*	stop_gained	Exon 29 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A1	ENST00000225964.10 link	c.3076C>T	p.Arg1026*	stop_gained	Exon 42 of 51	1	NM_000088.4	ENSP00000225964.6	P02452
COL1A1	ENST00000511732.1 link	n.20C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
COL1A1	ENST00000486572.1 link	n.-211C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL1A1: PVS1, PM2, PS4:Moderate -

Apr 27, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. In some published literature, this variant is referred to as R848X. -

Mar 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL1A1 c.3076C>T; p.Arg1026Ter variant (rs72653173), also known as p.Arg848Ter, is reported in the literature in multiple individuals and families affected with osteogenesis imperfecta type1 (Duan 2016, Ries 2000, Ries-Levavi 2004). This variant is reported in ClinVar (Variation ID: 35920) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Duan H et al. Identification of two recurrent mutations of COL1A1 gene in Chinese Van der Hoeve syndrome patients. Acta Otolaryngol. 2016 Aug;136(8):786-91. PMID: 27044453. Ries L et al. Prenatal diagnosis of a novel COL1A1 mutation in osteogenesis imperfecta type I carried through full term pregnancy. Prenat Diagn. 2000 Nov;20(11):876-80. PMID: 11113887. Ries-Levavi L et al. Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients. Hum Mutat. 2004 Apr;23(4):399-400. PMID: 15024745. -

Dec 26, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26627451, 36709916, 37079061, 37334733, 37270749, 35909573, 34902613, 36951356, 29499418, 28396251, 15024745, 17392686, 23682531, 27044453, 22753364, 24767406, 15241796, 31447884, 30692697, 30715774, 32770541, 34358384, 32166892, 37810882, 38807347, 11113887, 21667357) -

Osteogenesis imperfecta

Pathogenic:2

Aug 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Osteogenesis imperfecta type I

Pathogenic:2

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1026*) in the COL1A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with osteogenesis imperfecta, type 1 (PMID: 11113887, 27044453). ClinVar contains an entry for this variant (Variation ID: 35920). For these reasons, this variant has been classified as Pathogenic. -

Feb 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL1A1 c.3076C>T (p.Arg1026X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251366 control chromosomes. c.3076C>T has been reported in the literature in multiple individuals affected with Osteogenesis imperfecta type I (example: Hartikka_2004, Ries_2000, Ries-Levavi_2004). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Specifically, it was demonstrated that the variant resulted in a significant reduction in COL1A1 mRNA production (example: Kaneto_2014). The following publications have been ascertained in the context of this evaluation (PMID: 15241796, 24767406, 15024745, 11113887). ClinVar contains an entry for this variant (Variation ID: 35920). Based on the evidence outlined above, the variant was classified as pathogenic. -

Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029456: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;C5436842:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

Pathogenic:1

May 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the skeletal system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL1A1-related disorder

Pathogenic:1

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL1A1 c.3076C>T variant is predicted to result in premature protein termination (p.Arg1026*). This variant has been reported in multiple unrelated individuals with osteogenesis imperfecta type 1 (for example, see : Ries-Levavi et al. 2004. PubMed ID: 15024745; Hartikka et al. 2004. PubMed ID: 15241796; Table S1, Li et al. 2019. PubMed ID: 30715774). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Infantile cortical hyperostosis;C0029434:Osteogenesis imperfecta;C4551623:Ehlers-Danlos syndrome, arthrochalasia type

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 06-26-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.91

Vest4

0.95

GERP RS

1.6

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over