ClinVar Genomic variation as it relates to human health
NM_001369.3(DNAH5):c.4348C>T (p.Gln1450Ter)
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.4348C>T (p.Gln1450Ter)
Variation ID: 208992 Accession: VCV000208992.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p15.2 5: 13865675 (GRCh38) [ NCBI UCSC ] 5: 13865784 (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 Sep 29, 2015 May 1, 2024 Dec 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001369.3:c.4348C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001360.1:p.Gln1450Ter nonsense NC_000005.10:g.13865675G>A NC_000005.9:g.13865784G>A NG_013081.2:g.83806C>T - Protein change
- Q1450*
- Other names
- -
- Canonical SPDI
- NC_000005.10:13865674:G:A
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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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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
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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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DNAH5 | - | - |
GRCh38 GRCh37 |
5588 | 5834 |
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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not provided (1) |
no classification provided
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- | RCV000190910.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2021 | RCV000477807.13 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2023 | RCV000814567.19 |
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
(-)
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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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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073051.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
The stop gained p.Q1450* in DNAH5 (NM_001369.3) has been previously reported in homozygous state in affected individuals including those of Amish origin (Ferkol TW et … (more)
The stop gained p.Q1450* in DNAH5 (NM_001369.3) has been previously reported in homozygous state in affected individuals including those of Amish origin (Ferkol TW et al; Strauss KA et al). The variant has been submitted to ClinVar as Pathogenic. Although the variant is present at 0.0004% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.Q1450* variant is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Decreased serum testosterone concentration (present) , Abnormal pituitary gland morphology (present) , Primary amenorrhea (present) , Abnormality of the ovary (present)
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Pathogenic
(Oct 27, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810547.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 16, 2023)
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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: SCV000954980.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1450*) 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.Gln1450*) 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 (rs771663107, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 19357118, 23477994). ClinVar contains an entry for this variant (Variation ID: 208992). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 08, 2014)
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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: SCV002632192.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q1450* pathogenic mutation (also known as c.4348C>T) located in coding exon 27 of the DNAH5 gene, results from a C to T substitution at … (more)
The p.Q1450* pathogenic mutation (also known as c.4348C>T) located in coding exon 27 of the DNAH5 gene, results from a C to T substitution at nucleotide position 4348. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Eight members of a consanguineous Amish family from Pennsylvania who all had neonatal respiratory distress, situs inversus totalis, chronic pneumonia, or rhinosinusitis were found to be homozygous for this mutation. This paper also identified four additional affected individuals who were either homozygous or heterozygous (phase was confirmed trans through parental testing) for this mutation (Ferkol TW, et al. J. Pediatr. 2013 Aug; 163(2):383-7). Another study identified two affected individuals who each carried another mutation, Q3455H and E4133*, in conjunction with this mutation; however, phase was not specified (Failly M, et al. J. Med. Genet. 2009 Apr; 46(4):281-6). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
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Pathogenic
(Apr 27, 2016)
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no assertion criteria provided
Method: research
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Primary ciliary dyskinesia 3
Affected status: unknown
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536766.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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Pathogenic
(Jan 19, 2021)
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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: SCV002080951.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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: SCV002106439.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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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: SCV000245796.2
First in ClinVar: Sep 29, 2015 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 |
Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities. | Ferkol TW | The Journal of pediatrics | 2013 | PMID: 23477994 |
Genetics, medicine, and the Plain people. | Strauss KA | Annual review of genomics and human genetics | 2009 | PMID: 19630565 |
Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia. | Failly M | Journal of medical genetics | 2009 | PMID: 19357118 |
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 |
Text-mined citations for rs771663107 ...
HelpRecord last updated Jun 02, 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.