chr17-50189702-G-A

Variant names:

• chr17-50189702-G-A
• rs72653147
• NM_000088.4:c.2644C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000088.4(COL1A1):​c.2644C>T​(p.Arg882*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: COL1A1 NM_000088.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 2.81

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]

ACMG classification

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 17-50189702-G-A is Pathogenic according to our data. Variant chr17-50189702-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 456753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50189702-G-A is described in Lovd as [Pathogenic]. Variant chr17-50189702-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2644C>T	p.Arg882*	stop_gained	Exon 38 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2446C>T	p.Arg816*	stop_gained	Exon 35 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.2644C>T	p.Arg882*	stop_gained	Exon 38 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.1726C>T	p.Arg576*	stop_gained	Exon 25 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2644C>T	p.Arg882*	stop_gained	Exon 38 of 51	1	NM_000088.4	ENSP00000225964.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Nov 11, 2023

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, 31414283, 25533962, 21667357, 16786509, 22753364, 30614853, 27044453, 33939306, 33166682, 35476365, 15241796) -

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Human Development and Health, University of Southampton

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

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Jun 27, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Osteogenesis imperfecta Pathogenic:1

Jan 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Cardiovascular phenotype Pathogenic:1

Dec 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R882* pathogenic mutation (also known as c.2644C>T), located in coding exon 38 of the COL1A1 gene, results from a C to T substitution at nucleotide position 2644. This changes the amino acid from an arginine to a stop codon within coding exon 38. This variant was reported in individual(s) with features consistent with COL1A1-related osteogenesis imperfecta/ overlap disorders (Hartikka H et al. Hum Mutat, 2004 Aug;24:147-54; Fuccio A et al. J Mol Diagn, 2011 Nov;13:648-56; Zhang ZL et al. J Bone Miner Metab, 2012 Jan;30:69-77; Lin HY et al. Orphanet J Rare Dis, 2015 Dec;10:152; Ju M et al. J Bone Miner Metab, 2020 Mar;38:188-197; Redman MG et al. Eur J Med Genet, 2020 Dec;63:104095; Higuchi Y et al. Mol Genet Genomic Med, 2021 Jun;9:e1675). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Osteogenesis imperfecta type I Pathogenic:1

Jan 28, 2025

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.Arg882*) 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 I (PMID: 15241796, 21667357, 22753364, 26627451, 27044453). ClinVar contains an entry for this variant (Variation ID: 456753). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta;C4551623:Ehlers-Danlos syndrome, arthrochalasia type Other:1

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 08-03-2018 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	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.98
GERP RS		4.1

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

Other links and lift over

dbSNP: rs72653147; hg19: chr17-48267063; COSMIC: COSV56803025; COSMIC: COSV56803025;