ClinVar Genomic variation as it relates to human health
NM_012144.4(DNAI1):c.48+2dup
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012144.4(DNAI1):c.48+2dup
Variation ID: 5604 Accession: VCV000005604.55
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 34459054-34459055 (GRCh38) [ NCBI UCSC ] 9: 34459052-34459053 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 19, 2015 Oct 8, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012144.4:c.48+2dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_012144.4:c.48+2dupT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001281428.1:c.48+2dupT NM_001281428.2:c.48+2dup splice donor NM_012144.3:c.48+2dup NC_000009.12:g.34459055dup NC_000009.11:g.34459053dup NG_008127.1:g.5243dup NG_027971.1:g.4516dup - Protein change
- Other names
- IVS1+2_3insT
- 219+3insT
- Canonical SPDI
- NC_000009.12:34459054:T:TT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00040
Exome Aggregation Consortium (ExAC) 0.00046
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00048
Trans-Omics for Precision Medicine (TOPMed) 0.00048
The Genome Aggregation Database (gnomAD) 0.00050
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 | ||
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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. |
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DNAI1 | - | - |
GRCh38 GRCh37 |
883 | 966 |
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. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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May 22, 2023 | RCV000005954.25 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000230151.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2014 | RCV001266708.10 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Feb 7, 2022 | RCV000790798.25 | |
DNAI1-related disorder
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Pathogenic (1) |
no assertion criteria provided
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May 15, 2024 | RCV004754247.1 |
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. |
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Pathogenic
(Sep 26, 2014)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000224535.4
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967664.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The c.48+2dupT variant in DNAI1 is a well-known pathogenic founder variant (Zari wala 2006). It has been reported in >25 compound heterozygous or homozygous indi … (more)
The c.48+2dupT variant in DNAI1 is a well-known pathogenic founder variant (Zari wala 2006). It has been reported in >25 compound heterozygous or homozygous indi viduals with primary ciliary dyskinesia (PCD) with or without situs inversus (Ka rtagener syndrome) and segregated with disease in at least 2 affected relatives (Pennarun 1999, Guichard 2001, Zariwala 2006, Failly 2008, Li 2016, Paff 2018). This variant has been identified in 91/126580 European chromosomes, including on e homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs397515363). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicin g leading to an abnormal or absent protein. Functional studies provide some evid ence that this variant alters splicing, resulting in a truncated protein (Pennar un 1999, Zariwala 2006), and ultrastructural defects in the outer dynein arms we re observed in homozygous or compound heterozygous individuals (Guichard 2001, P aff 2018). In summary, this variant meets criteria to be classified as pathogeni c for primary ciliary dyskinesia in an autosomal recessive manner. ACMG/AMP Crit eria applied: PVS1_Strong, PM3_VeryStrong, PS3_Moderate, PP1. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Accession: SCV001810048.1
First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(Sep 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002072022.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
This sequence change has been described in the gnomAD database with a frequency of 0.073% in the non-Finnish European subpopulation (dbSNP rs1435805945). This sequence change … (more)
This sequence change has been described in the gnomAD database with a frequency of 0.073% in the non-Finnish European subpopulation (dbSNP rs1435805945). This sequence change has previously been described in several individuals with DNAI1-related primary ciliary dyskinesia in both homozygous and compound heterozygous state (PMIDs: 16858015, 33131162, 10577904, and 18434704). Functional studies showed that this 1-bp insertion impacts RNA splicing (PMID: 10577904. c.48+2dup is a common founder mutation in primary ciliary dyskinesia (PMID: 16858015) and is also reported with alternative nomenclatures such as c.48+2_48+3insT and IVS+2_3insT in the literature. (less)
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Pathogenic
(Feb 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001782235.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant demonstrated to result in loss-of-function (Pennarun et al., 1999) in a gene for which loss-of-function is a known mechanism of disease; … (more)
Canonical splice site variant demonstrated to result in loss-of-function (Pennarun et al., 1999) in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301301, 23477994, 11231901, 10577904, 26918822, 29363216, 18434704, 30290127, 16858015, 31772028, 31879361, 31980526, 33131162, 33726816, 27535533) (less)
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Pathogenic
(Sep 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Kartagener syndrome
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807545.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 strong, PS3 supporting, PM2 moderated, PM3 very strong
Number of individuals with the variant: 1
Clinical Features:
Neonatal respiratory distress (present) , Abnormal delivery (present) , Situs inversus (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Kartagener syndrome
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004024533.2
First in ClinVar: Aug 19, 2023 Last updated: Nov 11, 2023 |
Comment:
This DNAI1 canonical splice variant has been reported in many individuals with primary ciliary dyskinesia 1. This variant (rs1435805945) is rare (<0.1%) in a large … (more)
This DNAI1 canonical splice variant has been reported in many individuals with primary ciliary dyskinesia 1. This variant (rs1435805945) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 113/282694 total alleles; 0.04%; 1 homozygote), and has been reported in ClinVar4 (Variation ID 5604). This variant destroys a canonical donor site, is predicted to cause abnormal gene splicing and has supporting functional evidence. We consider c.48+2dup in DNAI1 to be pathogenic. (less)
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Pathogenic
(Dec 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Kartagener syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003823290.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000289879.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 1 of the DNAI1 gene. It does not directly change the encoded amino acid sequence of the DNAI1 protein. … (more)
This sequence change falls in intron 1 of the DNAI1 gene. It does not directly change the encoded amino acid sequence of the DNAI1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs755575751, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individuals with primary ciliary dyskinesia (PMID: 10577904, 11231901, 16858015, 18434704). This variant is also known as c.48+2_48+3insT and IVS+2_3insT. ClinVar contains an entry for this variant (Variation ID: 5604). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in partial retention of intron 1 and introduces a premature termination codon (PMID: 10577904). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Kartagener syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002783993.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 06, 2014)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444885.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Recurrent infections (present) , Bronchitis (present) , Chronic sinusitis (present) , Primary dilated cardiomyopathy (present) , Situs ambiguus (present)
Sex: female
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Pathogenic
(Dec 01, 1999)
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no assertion criteria provided
Method: literature only
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CILIARY DYSKINESIA, PRIMARY, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026136.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 19, 2015 |
Comment on evidence:
In a 9-year-old boy with immotile cilia syndrome (244400) unassociated with situs inversus, Pennarun et al. (1999) found compound heterozygosity for 2 mutations in the … (more)
In a 9-year-old boy with immotile cilia syndrome (244400) unassociated with situs inversus, Pennarun et al. (1999) found compound heterozygosity for 2 mutations in the DNAI1 gene: a 1-bp insertion (T) at nucleotide +3 of the intronic splice donor sequence following exon 1, which was inherited from his father, and a 4-bp insertion (AATA) at codon 95 (604366.0002), which was inherited from his mother. The paternal insertion resulted in the introduction of a HpaI site, while the maternal insertion resulted in a frameshift leading to a premature stop codon 24 amino acids downstream. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458177.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Kartagener syndrome
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760235.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742588.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955632.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely pathogenic
(Aug 01, 2018)
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no assertion criteria provided
Method: literature only
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Primary ciliary dyskinesia
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106460.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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Pathogenic
(May 15, 2024)
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no assertion criteria provided
Method: clinical testing
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DNAI1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005351108.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The DNAI1 c.48+2dupT variant is predicted to result in an intronic duplication. This variant is a well-documented founder variant and known cause of autosomal recessive … (more)
The DNAI1 c.48+2dupT variant is predicted to result in an intronic duplication. This variant is a well-documented founder variant and known cause of autosomal recessive primary ciliary dyskinesia (PCD) and Kartagener syndrome (Pennarun et al. 1999. PubMed ID: 10577904; Zariwala et al. 2006. PubMed ID: 16858015; Failly et al. 2008. PubMed ID: 18434704). In the literature, this variant is also reported as IVS1+2_3insT or c.48+2_48+3insT. This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799471.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809722.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968588.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Kartagener syndrome
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000086953.3
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype. | Davis SD | American journal of respiratory and critical care medicine | 2019 | PMID: 30067075 |
Primary Ciliary Dyskinesia. | Adam MP | - | 2019 | PMID: 20301301 |
Diagnostic yield of a targeted gene panel in primary ciliary dyskinesia patients. | Paff T | Human mutation | 2018 | PMID: 29363216 |
DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. | Li Y | PLoS genetics | 2016 | PMID: 26918822 |
Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities. | Ferkol TW | The Journal of pediatrics | 2013 | PMID: 23477994 |
Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD). | Ziętkiewicz E | Respiratory research | 2010 | PMID: 21143860 |
DNAI1 mutations explain only 2% of primary ciliary dykinesia. | Failly M | Respiration; international review of thoracic diseases | 2008 | PMID: 18434704 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. | Zariwala MA | American journal of respiratory and critical care medicine | 2006 | PMID: 16858015 |
Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome). | Guichard C | American journal of human genetics | 2001 | PMID: 11231901 |
Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. | Pennarun G | American journal of human genetics | 1999 | PMID: 10577904 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs397515363 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.