ClinVar Genomic variation as it relates to human health
NM_012144.4(DNAI1):c.1612G>A (p.Ala538Thr)
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.
Pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012144.4(DNAI1):c.1612G>A (p.Ala538Thr)
Variation ID: 583106 Accession: VCV000583106.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 34514436 (GRCh38) [ NCBI UCSC ] 9: 34514434 (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 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012144.4:c.1612G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036276.1:p.Ala538Thr missense NM_001281428.2:c.1624G>A NP_001268357.1:p.Ala542Thr missense NM_012144.2:c.1612G>A NC_000009.12:g.34514436G>A NC_000009.11:g.34514434G>A NG_008127.1:g.60624G>A - Protein change
- A538T, A542T
- Other names
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- Canonical SPDI
- NC_000009.12:34514435: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
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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DNAI1 | - | - |
GRCh38 GRCh37 |
880 | 961 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV000707353.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 28, 2020 | RCV001706703.3 |
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
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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
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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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Uncertain significance
(Sep 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Kartagener syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934555.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Pathogenic
(Jan 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506416.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
ACMG categories: PS4,PM1,PM2,PM3,PP1,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Primary ciliary dyskinesia (present)
Age: 0-9 years
Sex: female
Tissue: blood
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Pathogenic
(Dec 14, 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: SCV000836446.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 538 of the DNAI1 protein (p.Ala538Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 538 of the DNAI1 protein (p.Ala538Thr). This variant is present in population databases (rs368248592, gnomAD 0.01%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16858015, 21143860). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 583106). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAI1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 10, 2015)
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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: SCV002705252.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A538T pathogenic mutation (also known as c.1612G>A), located in coding exon 17 of the DNAI1 gene, results from a G to A substitution at … (more)
The p.A538T pathogenic mutation (also known as c.1612G>A), located in coding exon 17 of the DNAI1 gene, results from a G to A substitution at nucleotide position 1612. The alanine at codon 538 is replaced by threonine, an amino acid with some similar properties. This alteration was first reported in two unrelated individuals with symptoms of PCD with a second pathogenic alteration (confirmed in trans in one patient); both patients had outer dynein arm defects identified by ultrastructual analysis (Zariwala MA et al. Am J Respir Crit Care Med. 2006;174(8):858-66). In addition, this alteration was identified in the homozygous state in three families and in conjunction with another pathogenic mutation in an additional two patients, all who had symptoms of PCD and dynein arm defects; authors suggest this alteration may be a Polish founder mutation (Zitkiewicz E et al. Respir Res. 2010;11:174). Based on the supporting evidence, p.A538T is interpreted as a disease-causing mutation. (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: SCV001462308.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 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: SCV002106459.1 First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 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 |
Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD). | Ziętkiewicz E | Respiratory research | 2010 | PMID: 21143860 |
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 |
Text-mined citations for rs368248592 ...
HelpRecord last updated May 12, 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.