VCV000425580.19 - ClinVar

NM_000088.4(COL1A1):c.1821+1G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000088.4(COL1A1):c.1821+1G>A

Variation ID: 425580 Accession: VCV000425580.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.33 17: 50192993 (GRCh38) [ NCBI UCSC ] 17: 48270354 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Aug 25, 2024	Dec 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000088.4:c.1821+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000017.11:g.50192993C>T
NC_000017.10:g.48270354C>T
NG_007400.1:g.13647G>A
LRG_1:g.13647G>A
LRG_1t1:c.1821+1G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS26DS, G-A, +1

Canonical SPDI

NC_000017.11:50192992:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA291544536 OMIM: 120150.0046 dbSNP: rs66555264 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL1A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2756	2960

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Osteogenesis imperfecta type I	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 16, 2023	RCV000490727.9
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 6, 2023	RCV000599354.8
Ehlers-Danlos syndrome, arthrochalasia type Infantile cortical hyperostosis Osteogenesis imperfecta type I Osteogenesis imperfecta type III Osteogenesis imperfecta with normal sclerae, dominant form Osteogenesis imperfecta, perinatal lethal Postmenopausal osteoporosis	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763410.2
Osteogenesis imperfecta	Pathogenic (1)	criteria provided, single submitter	Apr 10, 2022	RCV002221545.2
COL1A1-related disorder	Pathogenic (1)	criteria provided, single submitter	Jul 13, 2023	RCV004551601.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 23, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000841063.1 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Publications: PubMed (4) PubMed: 17078022‚ 8408653‚ 9067755‚ 10931857
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile cortical hyperostosis Ehlers-Danlos syndrome, arthrochalasia type Osteogenesis imperfecta type I Osteogenesis imperfecta, perinatal lethal Osteogenesis imperfecta with normal sclerae, dominant form Osteoporosis Osteogenesis imperfecta type III Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894139.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Osteogenesis imperfecta type I Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140690.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Apr 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta Affected status: yes Allele origin: germline	DASA Accession: SCV002498810.1 First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022	Publications: PubMed (6) PubMed: 8408653‚ 33939306‚ 33928192‚ 28810924‚ 32166892‚ 33228694 Comment: The c.1821+1G>A variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region … (more) The c.1821+1G>A variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8408653) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:425580; PMID: 33939306; PMID: 33928192; PMID: 28810924; PMID: 32166892) - PS4. This variant is not present in population databases (rs66555264- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 33928192; 33228694) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Jul 19, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000709943.5 First in ClinVar: Apr 02, 2018 Last updated: Mar 04, 2023	Comment: Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stover et al., 1993); Not observed in large population … (more) Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stover et al., 1993); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25944380, 8408653, 25525159, 10931857, 9295084, 7942841, 9443882, 30614853, 9067755, 28810924, 33470886, 33939306, 17078022, 15931785) (less)
Pathogenic (Jul 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	COL1A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105013.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The COL1A1 c.1821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported to be causative for … (more) The COL1A1 c.1821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported to be causative for osteogenesis imperfecta (Stover et al. 1993. PubMed ID: 8408653; Zhytnik et al. 2020. PubMed ID: 32166892; Higuchi et al. 2021. PubMed ID: 33939306). mRNA studies showed that this variant results in intron 26 retention leading to a frameshift and premature protein termination (Stover et al. 1993. PubMed ID: 8408653). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Aug 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Osteogenesis imperfecta type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000752560.6 First in ClinVar: Jun 10, 2017 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 8408653‚ 9067755‚ 10931857‚ 15931785‚ 17078022‚ 16199547‚ 7942841‚ 9295084‚ 9443882 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 425580). This variant is also known as IVS26+1G>A. Disruption of this splice site has been observed in individuals with osteogenesis imperfecta (PMID: 8408653, 9067755, 10931857, 15931785, 17078022). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 of the COL1A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). (less)
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197553.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Oct 01, 1993)	no assertion criteria provided Method: literature only	OSTEOGENESIS IMPERFECTA, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039152.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 8408653‚ 2542316 Comment on evidence: Stover et al. (1993) demonstrated defective splicing of mRNA from one COL1A1 allele in a patient with mild type I OI (166200). Genovese et al. … (more) Stover et al. (1993) demonstrated defective splicing of mRNA from one COL1A1 allele in a patient with mild type I OI (166200). Genovese et al. (1989) had demonstrated that dermal fibroblasts from this patient showed a novel species of COL1A1 mRNA in the nuclear compartment of cells; that it was not collinear with a cDNA probe, and, therefore, with the fully spliced COL1A1 mRNA, was indicated by indirect RNase protection assays. Stover et al. (1993) showed that a G-to-A transition in the first position of the donor site of intron 26 resulted in the inclusion of the entire sequence in the mature mRNA that accumulated in the nuclear compartment. The retained intron contained an in-frame stop codon and introduced an out-of-frame insertion within the collagen mRNA producing stop codons downstream of the insertion. These changes probably accounted for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations within collagen mRNA that resulted in exon skipping and a truncated but in-frame RNA transcript, this mutation did not result in production of a defective COL1A1 chain. Instead, the mild nature of the disease in this patient reflected failure to process a defective mRNA and, thus, the absence of a protein product from the mutant allele. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	OI type I Affected status: yes Allele origin: unknown	Department of Medical Sciences, Uppsala University Additional submitter: Department of Dental Medicine, Karolinska Institutet Accession: SCV000574571.1 First in ClinVar: Jun 10, 2017 Last updated: Jun 10, 2017	Publications: PubMed (1) PubMed: 25944380 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1

Comment:

The c.1821+1G>A variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8408653) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:425580; PMID: 33939306; PMID: 33928192; PMID: 28810924; PMID: 32166892) - PS4. This variant is not present in population databases (rs66555264- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 33928192; 33228694) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic

Comment:

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stover et al., 1993); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25944380, 8408653, 25525159, 10931857, 9295084, 7942841, 9443882, 30614853, 9067755, 28810924, 33470886, 33939306, 17078022, 15931785)

Comment:

The COL1A1 c.1821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported to be causative for osteogenesis imperfecta (Stover et al. 1993. PubMed ID: 8408653; Zhytnik et al. 2020. PubMed ID: 32166892; Higuchi et al. 2021. PubMed ID: 33939306). mRNA studies showed that this variant results in intron 26 retention leading to a frameshift and premature protein termination (Stover et al. 1993. PubMed ID: 8408653). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 425580). This variant is also known as IVS26+1G>A. Disruption of this splice site has been observed in individuals with osteogenesis imperfecta (PMID: 8408653, 9067755, 10931857, 15931785, 17078022). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 of the COL1A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands.	Higuchi Y	Molecular genetics & genomic medicine	2021	PMID: 33939306
Abnormal corneal properties in osteogenesis imperfecta and glaucoma: a case series.	Doolan E	BMJ open ophthalmology	2021	PMID: 33928192
RNA sequencing analysis reveals increased expression of interferon signaling genes and dysregulation of bone metabolism affecting pathways in the whole blood of patients with osteogenesis imperfecta.	Zhytnik L	BMC medical genomics	2020	PMID: 33228694
Inter- and Intrafamilial Phenotypic Variability in Individuals with Collagen-Related Osteogenesis Imperfecta.	Zhytnik L	Clinical and translational science	2020	PMID: 32166892
Mutational analysis of COL1A1 and COL1A2 genes among Estonian osteogenesis imperfecta patients.	Zhytnik L	Human genomics	2017	PMID: 28810924
Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta.	Lindahl K	European journal of human genetics : EJHG	2015	PMID: 25944380
Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans.	Marini JC	Human mutation	2007	PMID: 17078022
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
[Mutation detection of COL1A1 gene in a pedigree with osteogenesis imperfecta].	Qin W	Yi chuan xue bao = Acta genetica Sinica	2005	PMID: 15931785
Tracking COL1A1 RNA in osteogenesis imperfecta. splice-defective transcripts initiate transport from the gene but are retained within the SC35 domain.	Johnson C	The Journal of cell biology	2000	PMID: 10931857
Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations.	Körkkö J	American journal of human genetics	1998	PMID: 9443882
Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen.	Byers PH	American journal of medical genetics	1997	PMID: 9295084
Two new recurrent nucleotide mutations in the COL1A1 gene in four patients with osteogenesis imperfecta: about one-fifth are recurrent.	Körkkö J	Human mutation	1997	PMID: 9067755
Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen.	Willing MC	American journal of human genetics	1994	PMID: 7942841
Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.	Stover ML	The Journal of clinical investigation	1993	PMID: 8408653
Detection of mutations in human type I collagen mRNA in osteogenesis imperfecta by indirect RNase protection.	Genovese C	The Journal of biological chemistry	1989	PMID: 2542316
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Text-mined citations for rs66555264 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000088.4(COL1A1):c.1821+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs66555264 ...