ClinVar Genomic variation as it relates to human health
NM_033124.5(CCDC65):c.877_878del (p.Ile293fs)
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_033124.5(CCDC65):c.877_878del (p.Ile293fs)
Variation ID: 88685 Accession: VCV000088685.48
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 12q13.12 12: 48918751-48918752 (GRCh38) [ NCBI UCSC ] 12: 49312534-49312535 (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 Feb 20, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033124.5:c.877_878del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149115.2:p.Ile293fs frameshift NM_001286957.2:c.448_449del NP_001273886.1:p.Ile150fs frameshift NM_033124.4:c.877_878del NC_000012.12:g.48918752AT[1] NC_000012.11:g.49312535AT[1] NG_033837.1:g.19643AT[1] - Protein change
- I293fs, I150fs
- Other names
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- Canonical SPDI
- NC_000012.12:48918750:TATAT:TAT
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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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CCDC65 | - | - |
GRCh38 GRCh37 |
231 | 242 |
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
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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 29, 2024 | RCV000074368.18 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 30, 2015 | RCV000215832.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2023 | RCV000599342.10 |
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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Likely pathogenic
(Nov 30, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271209.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Ile293fs variant in CCDC65 has been previously reported in 3 Ashkenazi Jew ish individuals with primary ciliary dyskinesia (PCD) and segregated with diseas e … (more)
The p.Ile293fs variant in CCDC65 has been previously reported in 3 Ashkenazi Jew ish individuals with primary ciliary dyskinesia (PCD) and segregated with diseas e in 1 affected family member (Austin-Tse 2013, Horani 2013). All of these indiv iduals were homozygous for the variant. This variant has also been identified in 20/66728 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org) and in 0.14% (3/2070) of chromosomes from an Ashkenazi Jewish control cohort (Fedick 2015). Although this variant has been seen in the general population, its frequency is still low enough to be consistent with a r ecessive carrier frequency. The p.Ile293fs variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 293 and leads to a premature termination codon 2 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In vitro studie s have demonstrated that the CCDC65 protein was absent in cells derived from an individual homozygous for this variant (Horani 2013). Functional studies in huma n cell lines and the zebrafish model provided some evidence that loss of functio n of the CCDC65 gene may cause cilia motility defects (Horani 2013, Austin-Tse 2 013), though these types of assays may not accurately reflect biological functio n. The p.Ile293fs variant is currently the only variant in CCDC65 gene that has been reported in individuals with PCD, therefore additional studies are needed t o fully understand the role of the CCDC65 gene in disease. In summary, although additional studies are required to fully establish its clinical significance, th e p.Ile293fs variant is likely pathogenic. (less)
Number of individuals with the variant: 5
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 27
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001381480.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile293Profs*2) in the CCDC65 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ile293Profs*2) in the CCDC65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC65 are known to be pathogenic (PMID: 23991085, 24094744). This variant is present in population databases (rs748630203, gnomAD 0.4%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23991085, 24094744). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 23991085, 24094744). This variant is also known as 876_877delAT. ClinVar contains an entry for this variant (Variation ID: 88685). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 27
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002051812.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
CCDC65 c.877_878del has been reported in the homozygous state in multiple individuals with primary ciliary dyskinesia. This variant (rs1272967209) has an entry in ClinVar and … (more)
CCDC65 c.877_878del has been reported in the homozygous state in multiple individuals with primary ciliary dyskinesia. This variant (rs1272967209) has an entry in ClinVar and has been identified in a large population dataset. The minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the Ashkenazi Jewish subpopulation (gnomAD: 45/10370 alleles; 0.4339%, no homozygotes). This frameshift variant results in a premature stop codon in exon 6 of 8 likely leading to nonsense-mediated decay and lack of protein production. We consider CCDC65 c.877_878del to be pathogenic. (less)
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Likely pathogenic
(Jun 30, 2023)
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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: SCV000710000.4
First in ClinVar: Apr 02, 2018 Last updated: Jul 08, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 24094744, 23991085, 34693619) (less)
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Pathogenic
(Oct 03, 2013)
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no assertion criteria provided
Method: literature only
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CILIARY DYSKINESIA, PRIMARY, 27, WITHOUT SITUS INVERSUS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000105975.4
First in ClinVar: Nov 10, 2013 Last updated: Nov 29, 2018 |
Comment on evidence:
In 2 brothers of Ashkenazi Jewish descent with primary ciliary dyskinesia-27 without situs inversus (CILD27; 615504), Austin-Tse et al. (2013) identified a homozygous 2-bp deletion, … (more)
In 2 brothers of Ashkenazi Jewish descent with primary ciliary dyskinesia-27 without situs inversus (CILD27; 615504), Austin-Tse et al. (2013) identified a homozygous 2-bp deletion, which they reported as 877_878delAT, in exon 6 of the CCDC65 gene, resulting in a frameshift and premature termination (Ile293ProfsTer2). An unrelated girl of Ashkenazi Jewish descent was also found to be homozygous for the mutation; her unaffected parents were heterozygous for the mutation. The patients had recurrent bronchitis, sinusitis, and/or otitis media. Fertility status could not be ascertained. Cilia ultrastructure showed normal outer dynein arms, radial spokes, and central pairs, but there was a reduction in inner dynein arms and nexin links. Microtubule disorganization was also observed in 5 to 15% of cilia cross-sections, suggesting that the reduction in nexin links may lead to overall structural instability in a subset of cilia. Live imaging of patient nasal epithelial cilia showed a stiff, dyskinetic cilia waveform. Horani et al. (2013) identified a homozygous 2-bp deletion (c.876_877delAT) in exon 6 of the CCDC65 gene in an 18-year-old boy of Ashkenazi Jewish descent with CILD27 without situs inversus. The deletion was predicted to result in a frameshift and premature termination at codon 293. The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 135) or Exome Variant Server databases. It was found in 3 of 733 Ashkenazi Jewish controls, indicating a carrier rate of 1 in 244. Patient nasal epithelial cilia showed a normal structure, but an abnormal stiff and hyperkinetic beating pattern compared to controls. Immunohistochemical studies of patient nasal epithelial cells showed absence of the CCDC65 protein as well as absence of GAS8 (605178). Similar results were obtained after shRNA knockdown of CCDC65 in control respiratory epithelial cells. (less)
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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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Modelling of primary ciliary dyskinesia using patient-derived airway organoids. | van der Vaart J | EMBO reports | 2021 | PMID: 34693619 |
Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population. | Fedick AM | Molecular genetics & genomic medicine | 2015 | PMID: 25802884 |
Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia. | Austin-Tse C | American journal of human genetics | 2013 | PMID: 24094744 |
CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia. | Horani A | PloS one | 2013 | PMID: 23991085 |
Text-mined citations for rs863223325 ...
HelpRecord last updated May 27, 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.