Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23255504, 22693295, 30067075, 22693285, 32253119, 31589614, 25525159, 20301301, 33988008, 31772028, 21131972)
ClinVar Genomic variation as it relates to human health
NM_181426.2(CCDC39):c.357+1G>C
Germline
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.
(11)
Help
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_181426.2(CCDC39):c.357+1G>C
Variation ID: 31067 Accession: VCV000031067.47
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q26.33 3: 180661860 (GRCh38) [ NCBI UCSC ] 3: 180379648 (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 Oct 1, 2013 Oct 20, 2024 Mar 11, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_181426.2:c.357+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000003.12:g.180661860C>G NC_000003.11:g.180379648C>G NG_029581.1:g.22636G>C - Protein change
- -
- Other names
-
IVS3DS, G-C, +1
c.357+1G>C
- Canonical SPDI
- NC_000003.12:180661859:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD), exomes 0.00016
Exome Aggregation Consortium (ExAC) 0.00037
- 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. |
|||
| CCDC39 | - | - |
GRCh38 GRCh37 |
645 | 864 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 22, 2022 | RCV000024061.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2024 | RCV000199155.17 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 12, 2024 | RCV001092443.27 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001327942.3 | |
|
CCDC39-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Dec 24, 2023 | RCV003914861.3 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 14
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003820606.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002050515.4
First in ClinVar: Jan 08, 2022 Last updated: Sep 29, 2024 |
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a … (more)
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23255504, 22693295, 30067075, 22693285, 32253119, 31589614, 25525159, 20301301, 33988008, 31772028, 21131972) (less)
|
|
|
Pathogenic
(Mar 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 14
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002803578.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jul 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 14
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807217.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 strong, PM3 strong
Number of individuals with the variant: 1
Clinical Features:
Cough (present) , Sinusitis (present) , Hyperemesis gravidarum (present) , Neonatal respiratory distress (present) , Dyspnea (present) , Maternal teratogenic exposure (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253975.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 3 of the CCDC39 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 3 of the CCDC39 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). This variant is present in population databases (rs397515392, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972, 22693295, 23255504). 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: 31067). 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)
|
|
|
Pathogenic
(Mar 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002613537.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.357+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the CCDC39 gene. This alteration was … (more)
The c.357+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the CCDC39 gene. This alteration was detected in the homozygous state, and in conjunction with another alteration in CCDC39, in multiple individuals with CCDC39-related primary ciliary dyskinesia ((Merveille AC et al. Nat Genet, 2011 Jan;43:72-8; Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Blanchon S et al. J Med Genet, 2020 Apr;57:237-244; Baz-Redón N et al. Arch Bronconeumol (Engl Ed), 2021 Mar;57:186-194). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
|
|
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Pathogenic
(Apr 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248959.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 01, 2011)
|
no assertion criteria provided
Method: literature only
|
CILIARY DYSKINESIA, PRIMARY, 14
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045352.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 30, 2017 |
Comment on evidence:
In affected members from 4 unrelated families with primary ciliary dyskinesia-14 (CILD14; 613807), Merveille et al. (2011) identified a G-to-C transversion in intron 3 of … (more)
In affected members from 4 unrelated families with primary ciliary dyskinesia-14 (CILD14; 613807), Merveille et al. (2011) identified a G-to-C transversion in intron 3 of the CCDC39 gene. Two sibs, of Turkish origin, were homozygous for the mutation, whereas the other 4 patients, including 2 unrelated individuals of French origin and 2 Danish sibs, were compound heterozygous for this mutation and another pathogenic mutation (see, e.g., 613798.0004). Haplotype analysis indicated a founder effect for the splice site mutation. (less)
|
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Pathogenic
(Dec 24, 2023)
|
no assertion criteria provided
Method: clinical testing
|
CCDC39-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004732343.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The CCDC39 c.357+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous and … (more)
The CCDC39 c.357+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with primary ciliary dyskinesia (Merveille et al. 2011. PubMed ID: 21131972; Blanchon et al. 2019. PubMed ID: 31772028; Baz-Redón et al. 2020. PubMed ID: 32253119). This variant is reported in 0.038% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in CCDC39 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
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pathologic
(Sep 15, 2011)
|
no assertion criteria provided
Method: curation
|
Primary Ciliary Dyskinesia
Affected status: not provided
Allele origin:
not provided
|
GeneReviews
Accession: SCV000087184.1
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: provider interpretation
|
Infertility disorder
Affected status: yes
Allele origin:
germline
|
MAGI's Lab - Research, MAGI Group
Accession: SCV001432720.1
First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021 |
|
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| click to load more click to collapse | |||||
Comment:
Comment:
ACMG classification criteria: PVS1 strong, PM3 strong
Comment:
This sequence change affects a donor splice site in intron 3 of the CCDC39 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). This variant is present in population databases (rs397515392, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972, 22693295, 23255504). 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: 31067). 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.
Comment:
The c.357+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the CCDC39 gene. This alteration was detected in the homozygous state, and in conjunction with another alteration in CCDC39, in multiple individuals with CCDC39-related primary ciliary dyskinesia ((Merveille AC et al. Nat Genet, 2011 Jan;43:72-8; Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Blanchon S et al. J Med Genet, 2020 Apr;57:237-244; Baz-Redón N et al. Arch Bronconeumol (Engl Ed), 2021 Mar;57:186-194). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
The CCDC39 c.357+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with primary ciliary dyskinesia (Merveille et al. 2011. PubMed ID: 21131972; Blanchon et al. 2019. PubMed ID: 31772028; Baz-Redón et al. 2020. PubMed ID: 32253119). This variant is reported in 0.038% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in CCDC39 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Converted during submission to 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:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23255504, 22693295, 30067075, 22693285, 32253119, 31589614, 25525159, 20301301, 33988008, 31772028, 21131972)
Comment:
ACMG classification criteria: PVS1 strong, PM3 strong
Comment:
This sequence change affects a donor splice site in intron 3 of the CCDC39 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). This variant is present in population databases (rs397515392, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972, 22693295, 23255504). 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: 31067). 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.
Comment:
The c.357+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the CCDC39 gene. This alteration was detected in the homozygous state, and in conjunction with another alteration in CCDC39, in multiple individuals with CCDC39-related primary ciliary dyskinesia ((Merveille AC et al. Nat Genet, 2011 Jan;43:72-8; Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Blanchon S et al. J Med Genet, 2020 Apr;57:237-244; Baz-Redón N et al. Arch Bronconeumol (Engl Ed), 2021 Mar;57:186-194). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
The CCDC39 c.357+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with primary ciliary dyskinesia (Merveille et al. 2011. PubMed ID: 21131972; Blanchon et al. 2019. PubMed ID: 31772028; Baz-Redón et al. 2020. PubMed ID: 32253119). This variant is reported in 0.038% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in CCDC39 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Implementation of a Gene Panel for Genetic Diagnosis of Primary Ciliary Dyskinesia. | Baz-Redón N | Archivos de bronconeumologia | 2021 | PMID: 32253119 |
| Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. | Blanchon S | Journal of medical genetics | 2020 | PMID: 31772028 |
| Primary Ciliary Dyskinesia. | Adam MP | - | 2019 | PMID: 20301301 |
| Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. | Antony D | Human mutation | 2013 | PMID: 23255504 |
| Umbilical bile staining in a patient with gall-bladder perforation. | Fisken E | BMJ case reports | 2011 | PMID: 22693295 |
| CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. | Merveille AC | Nature genetics | 2011 | PMID: 21131972 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs397515392 ...
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 Oct 20, 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.