ClinVar Genomic variation as it relates to human health
NM_001369.3(DNAH5):c.5563dup (p.Ile1855fs)
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_001369.3(DNAH5):c.5563dup (p.Ile1855fs)
Variation ID: 407241 Accession: VCV000407241.23
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 5p15.2 5: 13841051-13841052 (GRCh38) [ NCBI UCSC ] 5: 13841160-13841161 (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 Oct 10, 2018 May 1, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001369.3:c.5563dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001360.1:p.Ile1855fs frameshift NM_001369.2:c.5563dupA NC_000005.10:g.13841058dup NC_000005.9:g.13841167dup NG_013081.2:g.108429dup - Protein change
- I1855fs
- Other names
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- Canonical SPDI
- NC_000005.10:13841051:TTTTTTT:TTTTTTTT
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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DNAH5 | - | - |
GRCh38 GRCh37 |
5624 | 5870 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000475541.14 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2022 | RCV001198865.9 |
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
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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
(Mar 12, 2020)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 3
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369860.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP1,PP3.
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Pathogenic
(Oct 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 3
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002051792.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
DNAH5 c.5563dupA has been reported in multiple individuals with primary ciliary dyskinesia. This variant (rs752925056) is rare (<0.1%) in a large population dataset (gnomAD: 17/282580 … (more)
DNAH5 c.5563dupA has been reported in multiple individuals with primary ciliary dyskinesia. This variant (rs752925056) is rare (<0.1%) in a large population dataset (gnomAD: 17/282580 total alleles; 0.006%; no homozygotes) and has been reported in ClinVar. This frameshift variant results in a premature stop codon in exon 34 likely leading to nonsense-mediated decay and lack of protein production. We consider DNAH5 c.5563dupA to be pathogenic. (less)
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Pathogenic
(Jan 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 3
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002496126.1
First in ClinVar: Apr 11, 2022 Last updated: Apr 11, 2022 |
Comment:
ACMG categories: PVS1,PM3,PP5
Number of individuals with the variant: 1
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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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Invitae
Accession: SCV000546329.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile1855Asnfs*6) in the DNAH5 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ile1855Asnfs*6) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). This variant is present in population databases (rs752925056, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 11788826, 25186273, 26228299). ClinVar contains an entry for this variant (Variation ID: 407241). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 19, 2022)
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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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Ambry Genetics
Accession: SCV002653144.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.5563dupA pathogenic mutation, located in coding exon 34 of the DNAH5 gene, results from a duplication of A at nucleotide position 5563, causing a … (more)
The c.5563dupA pathogenic mutation, located in coding exon 34 of the DNAH5 gene, results from a duplication of A at nucleotide position 5563, causing a translational frameshift with a predicted alternate stop codon (p.I1855Nfs*6). This alteration has been detected in the homozygous state, or in conjunction with another DNAH5 mutation, in multiple individuals with primary ciliary dyskinesia (Hornef N et al. Am J Respir Crit Care Med, 2006 Jul;174:120-6; Guo Z et al. J Pediatr, 2020 10;225:157-165.e5; Kurokawa A et al. Respir Investig, 2021 Jul;59:550-554; Blanchon S et al. J Med Genet, 2020 04;57:237-244; Raidt J et al. Eur Respir J, 2014 Dec;44:1579-88; Djakow J et al. Pediatr Pulmonol, 2016 May;51:498-509). In addition, this alteration has been found to cosegregate with disease in four affected homozygous siblings with consanguineous parentage (Olbrich H et al. Nat. Genet., 2002 Feb;30:143-4; Omran H et al. Am. J. Respir. Cell Mol. Biol., 2000 Nov;23:696-702). 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. (less)
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Pathogenic
(Feb 01, 2002)
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no assertion criteria provided
Method: literature only
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CILIARY DYSKINESIA, PRIMARY, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027046.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a consanguineous Lebanese family in which 4 of 8 sibs had primary ciliary dyskinesia or Kartagener syndrome (608644), Olbrich et al. (2002) found a … (more)
In a consanguineous Lebanese family in which 4 of 8 sibs had primary ciliary dyskinesia or Kartagener syndrome (608644), Olbrich et al. (2002) found a homozygous 1-bp insertion in exon 34 of the DNAH5 gene, 5563insA. (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: SCV001457362.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Mar 25, 2021)
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no assertion criteria provided
Method: clinical testing
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Primary ciliary dyskinesia 3
Affected status: yes
Allele origin:
germline
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Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong
Accession: SCV002498737.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
This variant c.5563dupA(p.I1855fs) creates a premature termination codon in exon 34, where nonsense-mediated decay is predicted to occur. The mechanism of pathogenicity in DNAH5 mutations … (more)
This variant c.5563dupA(p.I1855fs) creates a premature termination codon in exon 34, where nonsense-mediated decay is predicted to occur. The mechanism of pathogenicity in DNAH5 mutations appears to be bi-allelic loss of function [PMID: 16627867] (PVS1). This variant is extremely rare in the gnomAD database (PM2). It was previously reported in patients with primary ciliary dyskinesia and atrial and ventricular septal defects and found to be in trans configuration with another damaging variant or as a homozygote [PMID: 11788826, 28991257, 31118369, 31772028, 32622824] (PM3). It is interpreted as pathogenic according to ACMG/AMP guidelines. (less)
Clinical Features:
Situs inversus (present) , Dextrocardia (present)
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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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Multifaceted analysis of Japanese cases of primary ciliary dyskinesia: Value of immunofluorescence for ciliary protein detection in patients with DNAH5 and DNAH11 mutations. | Kurokawa A | Respiratory investigation | 2021 | PMID: 33589394 |
Clinical and Genetic Spectrum of Children with Primary Ciliary Dyskinesia in China. | Guo Z | The Journal of pediatrics | 2020 | PMID: 32502479 |
Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. | Blanchon S | Journal of medical genetics | 2020 | PMID: 31772028 |
An effective combination of sanger and next generation sequencing in diagnostics of primary ciliary dyskinesia. | Djakow J | Pediatric pulmonology | 2016 | PMID: 26228299 |
Ciliary beat pattern and frequency in genetic variants of primary ciliary dyskinesia. | Raidt J | The European respiratory journal | 2014 | PMID: 25186273 |
DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. | Hornef N | American journal of respiratory and critical care medicine | 2006 | PMID: 16627867 |
Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. | Olbrich H | Nature genetics | 2002 | PMID: 11788826 |
Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene. | Omran H | American journal of respiratory cell and molecular biology | 2000 | PMID: 11062149 |
- | - | - | - | DOI: 10.1002/pd.6151 |
- | - | - | - | DOI: doi/10.1002/pd.6151 |
Text-mined citations for rs752925056 ...
HelpRecord last updated Jul 15, 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.