ClinVar Genomic variation as it relates to human health
NM_001364171.2(ODAD1):c.853G>A (p.Ala285Thr)
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_001364171.2(ODAD1):c.853G>A (p.Ala285Thr)
Variation ID: 39637 Accession: VCV000039637.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 48303953 (GRCh38) [ NCBI UCSC ] 19: 48807210 (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 30, 2013 May 12, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001364171.2:c.853G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351100.1:p.Ala285Thr missense NM_144577.4:c.742G>A NP_653178.3:p.Ala248Thr missense NC_000019.10:g.48303953C>T NC_000019.9:g.48807210C>T NG_033251.1:g.21123G>A - Protein change
- A248T, A285T
- Other names
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- Canonical SPDI
- NC_000019.10:48303952: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00022
The Genome Aggregation Database (gnomAD), exomes 0.00024
Trans-Omics for Precision Medicine (TOPMed) 0.00026
Exome Aggregation Consortium (ExAC) 0.00031
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
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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ODAD1 | - | - |
GRCh38 GRCh37 |
444 | 455 |
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 (2) |
criteria provided, single submitter
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Feb 16, 2022 | RCV000032837.9 | |
not provided (1) |
no classification provided
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- | RCV000190918.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2024 | RCV000231978.14 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2022 | RCV001579702.19 |
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
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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
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
(Dec 20, 2017)
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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: SCV002755180.2
First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024 |
Comment:
The c.742G>A pathogenic mutation (also known as p.A248T), located in coding exon 6 of the CCDC114 gene, results from a G to A substitution at … (more)
The c.742G>A pathogenic mutation (also known as p.A248T), located in coding exon 6 of the CCDC114 gene, results from a G to A substitution at nucleotide position 742. The amino acid change results in alanine to threonine at codon 248, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This mutation was identified in muliple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous state (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106; Onoufriadis A et al. Am. J. Hum. Genet., 2013 Jan;92:88-98; Boaretto F et al. J Mol Diagn, 2016 Nov;18:912-922). In addition, analysis of RNA from affected individuals homozygous for this alteration showed an insertion of 79 nucleotides, resulting in premature protein truncation (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106; Onoufriadis A et al. Am. J. Hum. Genet., 2013 Jan;92:88-98). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Feb 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 20
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893540.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002543953.11
First in ClinVar: Jul 09, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 02, 2019)
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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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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Accession: SCV001431737.2
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
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Pathogenic
(Jul 27, 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: SCV003761925.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Reported as a common pathogenic variant among individuals of Dutch Volendam background (Onoufriadis et al., 2013; Kos et al., 2022); Non-canonical splice site variant demonstrated … (more)
Reported as a common pathogenic variant among individuals of Dutch Volendam background (Onoufriadis et al., 2013; Kos et al., 2022); Non-canonical splice site variant demonstrated to result in loss of function (Onoufriadis et al., 2013); This variant is associated with the following publications: (PMID: 23261303, 20301301, 23261302, 35163670, 35343062) (less)
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Pathogenic
(Jan 06, 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: SCV000291388.9
First in ClinVar: Jul 01, 2016 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 248 of the CCDC114 protein (p.Ala248Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 248 of the CCDC114 protein (p.Ala248Thr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs147718607, gnomAD 0.05%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23261302, 23261303). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39637). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the use of a cryptic splice donor site and introduces a premature termination codon (PMID: 23261302). 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
(-)
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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: SCV001808187.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(Jan 10, 2013)
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no assertion criteria provided
Method: literature only
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CILIARY DYSKINESIA, PRIMARY, 20
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056606.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 18, 2021 |
Comment on evidence:
In affected members of a large multigenerational family from an isolated region of North Holland with primary ciliary dyskinesia-20 (CILD20; 615067), Onoufriadis et al. (2013) … (more)
In affected members of a large multigenerational family from an isolated region of North Holland with primary ciliary dyskinesia-20 (CILD20; 615067), Onoufriadis et al. (2013) identified a homozygous 742G-A transition affecting the final nucleotide of exon 7 of the CCDC114 gene, predicted to affected a splice site. Although the 742G-A change could also create an ala248-to-thr (A248T) substitution, this amino acid is not well conserved and was not predicted to be deleterious to protein structure. RT-PCR analysis of patient cells showed that the mutation caused an intronic insertion, resulting in a frameshift and premature termination (A248Tfs*52) with lack of a critical coiled-coil domain. Nasal epithelial cells showed decreased mutant mRNA compared to expression of wildtype mRNA in control cells, suggesting possible residual gene expression. However, respiratory epithelial cells showed abnormal ciliary motility with static cilia or few cilia with stiff, slow, twitching or flickering movement, and transmission electron microscopy showed loss of the outer dynein arms. The mutation was identified by exome sequencing of 2 individuals, segregated with the disorder, and was also found in 8 patients from 7 additional families from this region. This variant was present in the heterozygous state at a very low frequency, less than 1 in 3,200 alleles, in European controls from the NHLBI Exome Variant Server (rs147718607); this variant frequency would give a prevalence of homozygous cases of less than 1 in 40,000,000. Haplotype analysis of individuals in the largest family suggested a founder effect; the mutation was estimated to have occurred prior to the founding of the Volendam village in 1462. Simultaneously and independently, Knowles et al. (2013) identified a homozygous 742G-A mutation in the CCDC114 gene in 2 sibs with CILD20. Four patients from 3 additional families were found to be compound heterozygous for the 742G-A mutation and another pathogenic mutation in the CCDC114 gene (615038.0003-615038.0005). The 742G-A mutation was found in 3 (0.043%) of 7,020 control alleles. All patients with the mutation shared a common haplotype, consistent with a founder mutation. RT-PCR from patient cells with the 742G-A mutation yielded several different mutant transcript products, including A248Sfs*52 and E186X. However, cells from 1 patient with the 742G-A mutation showed faint amplification of full-length mRNA, suggesting that it may be a leaky mutation. (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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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: SCV001951692.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001964177.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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: SCV000245804.2
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. | Adam MP | - | 2019 | PMID: 20301301 |
Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients. | Boaretto F | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27637300 |
Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. | Onoufriadis A | American journal of human genetics | 2013 | PMID: 23261303 |
Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. | Knowles MR | American journal of human genetics | 2013 | PMID: 23261302 |
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 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs147718607 ...
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.