This sequence change in DNAH5 is predicted to replace arginine with glutamine at codon 1454, p.(Arg1454Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the coiled-coiled stem region. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.02% (199/1,179,988 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been observed in trans with a pathogenic variant in two siblings with primary ciliary dyskinesia in a single family (PMID: 11788826, 25186273). It has conflicting interpretations in ClinVar (ID: 287698). Computational evidence is uninformative for the missense substitution (REVEL = 0.510). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3, PM2_Supporting, PP1.
ClinVar Genomic variation as it relates to human health
NM_001369.3(DNAH5):c.4361G>A (p.Arg1454Gln)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)
5 out of 7 submissions contributed to this classification
Help
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.
7
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001369.3(DNAH5):c.4361G>A (p.Arg1454Gln)
Variation ID: 287698 Accession: VCV000287698.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p15.2 5: 13864632 (GRCh38) [ NCBI UCSC ] 5: 13864741 (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 Dec 6, 2016 Apr 13, 2025 Dec 13, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001369.3:c.4361G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001360.1:p.Arg1454Gln missense NC_000005.10:g.13864632C>T NC_000005.9:g.13864741C>T NG_013081.2:g.84849G>A Q8TE73:p.Arg1454Gln - Protein change
- R1454Q
- Other names
- -
- Canonical SPDI
- NC_000005.10:13864631:C:T
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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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0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| DNAH5 | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh37 |
5923 | 6170 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 9, 2016 | RCV000266533.6 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
May 22, 2024 | RCV000477841.8 | |
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Dec 13, 2024 | RCV001247795.13 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Feb 05, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812510.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in DNAH5 is predicted to replace arginine with glutamine at codon 1454, p.(Arg1454Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz … (more)
This sequence change in DNAH5 is predicted to replace arginine with glutamine at codon 1454, p.(Arg1454Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the coiled-coiled stem region. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.02% (199/1,179,988 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been observed in trans with a pathogenic variant in two siblings with primary ciliary dyskinesia in a single family (PMID: 11788826, 25186273). It has conflicting interpretations in ClinVar (ID: 287698). Computational evidence is uninformative for the missense substitution (REVEL = 0.510). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3, PM2_Supporting, PP1. (less)
|
|
|
Pathogenic
(Mar 24, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002632248.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R1454Q variant (also known as c.4361G>A), located in coding exon 28 of the DNAH5 gene, results from a G to A substitution at nucleotide … (more)
The p.R1454Q variant (also known as c.4361G>A), located in coding exon 28 of the DNAH5 gene, results from a G to A substitution at nucleotide position 4361. The arginine at codon 1454 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in two siblings with primary ciliary dyskensia (characterized by outer dynein arm defects on electron microscopy) who were compound heterozygous for another DNAH5 mutation; both siblings had immotile cilia and one sibling had situs inversus (Olbrich H, Nat. Genet. 2002 Feb; 30(2):143-4; Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Ex vivo cultures of these patients' epithelial airway showed absent cilia or membrane alterations in many cells and mislocalization of DNAH5 to the basal body region in the remaining cells (Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Based on the available evidence, p.R1454Q is classified as a pathogenic mutation. (less)
|
|
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Likely pathogenic
(May 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 3
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV005668914.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
|
|
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Likely pathogenic
(Dec 13, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001421238.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 16, 2025 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1454 of the DNAH5 protein (p.Arg1454Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1454 of the DNAH5 protein (p.Arg1454Gln). This variant is present in population databases (rs542708170, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 287698). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNAH5 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
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Uncertain significance
(Jun 09, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000341564.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
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Likely pathogenic
(Feb 10, 2016)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
Primary ciliary dyskinesia 3
Affected status: unknown
Allele origin:
germline
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536778.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
|
|
|
Uncertain significance
(Jan 17, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002080949.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
The p.R1454Q variant (also known as c.4361G>A), located in coding exon 28 of the DNAH5 gene, results from a G to A substitution at nucleotide position 4361. The arginine at codon 1454 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in two siblings with primary ciliary dyskensia (characterized by outer dynein arm defects on electron microscopy) who were compound heterozygous for another DNAH5 mutation; both siblings had immotile cilia and one sibling had situs inversus (Olbrich H, Nat. Genet. 2002 Feb; 30(2):143-4; Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Ex vivo cultures of these patients' epithelial airway showed absent cilia or membrane alterations in many cells and mislocalization of DNAH5 to the basal body region in the remaining cells (Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Based on the available evidence, p.R1454Q is classified as a pathogenic mutation.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1454 of the DNAH5 protein (p.Arg1454Gln). This variant is present in population databases (rs542708170, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 287698). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNAH5 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
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:
This sequence change in DNAH5 is predicted to replace arginine with glutamine at codon 1454, p.(Arg1454Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the coiled-coiled stem region. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.02% (199/1,179,988 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been observed in trans with a pathogenic variant in two siblings with primary ciliary dyskinesia in a single family (PMID: 11788826, 25186273). It has conflicting interpretations in ClinVar (ID: 287698). Computational evidence is uninformative for the missense substitution (REVEL = 0.510). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3, PM2_Supporting, PP1.
Comment:
The p.R1454Q variant (also known as c.4361G>A), located in coding exon 28 of the DNAH5 gene, results from a G to A substitution at nucleotide position 4361. The arginine at codon 1454 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in two siblings with primary ciliary dyskensia (characterized by outer dynein arm defects on electron microscopy) who were compound heterozygous for another DNAH5 mutation; both siblings had immotile cilia and one sibling had situs inversus (Olbrich H, Nat. Genet. 2002 Feb; 30(2):143-4; Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Ex vivo cultures of these patients' epithelial airway showed absent cilia or membrane alterations in many cells and mislocalization of DNAH5 to the basal body region in the remaining cells (Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Based on the available evidence, p.R1454Q is classified as a pathogenic mutation.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1454 of the DNAH5 protein (p.Arg1454Gln). This variant is present in population databases (rs542708170, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 287698). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNAH5 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Ciliary beat pattern and frequency in genetic variants of primary ciliary dyskinesia. | Raidt J | The European respiratory journal | 2014 | PMID: 25186273 |
| Axonemal localization of the dynein component DNAH5 is not altered in secondary ciliary dyskinesia. | Olbrich H | Pediatric research | 2006 | PMID: 16492982 |
| Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. | Olbrich H | Nature genetics | 2002 | PMID: 11788826 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DNAH5 | - | - | - | - |
Text-mined citations for rs542708170 ...
HelpThese 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 Apr 20, 2025
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.