VCV000139599.10 - ClinVar

NM_021147.5(CCNO):c.248_252dup (p.Gly85fs)

Germline

Classification

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.

(6)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021147.5(CCNO):c.248_252dup (p.Gly85fs)

Variation ID: 139599 Accession: VCV000139599.10

Type and length

Duplication, 5 bp

Location

Cytogenetic: 5q11.2 5: 55233271-55233272 (GRCh38) [ NCBI UCSC ] 5: 54529099-54529100 (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	Jul 11, 2014	Feb 7, 2023	Oct 1, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_021147.5:c.248_252dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066970.3:p.Gly85fs	frameshift
NR_125346.2:n.333_337dup		non-coding transcript variant
NR_125347.2:n.333_337dup		non-coding transcript variant
NC_000005.10:g.55233275_55233279dup
NC_000005.9:g.54529103_54529107dup
NG_034201.1:g.5442_5446dup

... more HGVS ... less HGVS

Protein change

G85fs

Other names

Canonical SPDI

NC_000005.10:55233271:GGGCAGGG:GGGCAGGGCAGGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA163288 OMIM: 607752.0001 dbSNP: rs587777498 VarSome

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
Gene	OMIM	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.
CCNO		-	-	GRCh38 GRCh37	161	199
LOC129993895	-	-	-	GRCh38	-	24

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.
Primary ciliary dyskinesia 29	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 26, 2022	RCV000128540.13
Primary ciliary dyskinesia	Pathogenic (2)	criteria provided, single submitter	Oct 1, 2022	RCV000472435.15

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 (Dec 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 29 Affected status: yes Allele origin: germline	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital Accession: SCV001499909.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (3) PubMed: 24747639‚ 30067075‚ 32367404 Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: East Asia Geographic origin: China
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 29 Affected status: yes Allele origin: germline	3billion Accession: SCV002058645.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:24747639 PMID:24747639 Comment: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported … (more) Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:24747639, PS3_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000139599, PMID:24747639). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000034, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal sputum (present) , Bronchiectasis (present) , Chronic sinusitis (present) , Failure to thrive (present) , Otitis media with effusion (present) , Recurrent lower respiratory … (more) Abnormal sputum (present) , Bronchiectasis (present) , Chronic sinusitis (present) , Failure to thrive (present) , Otitis media with effusion (present) , Recurrent lower respiratory tract infections (present) , Primary ciliary dyskinesia (present) (less)
Pathogenic (Apr 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 29 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002798505.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 01, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000552829.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 28492532‚ 24747639 Comment: This sequence change creates a premature translational stop signal (p.Gly85Cysfs11) in the CCNO gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gly85Cysfs11) in the CCNO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCNO are known to be pathogenic (PMID: 24747639). This variant is present in population databases (rs753409639, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital mucociliary clearance disorder (PMID: 24747639). ClinVar contains an entry for this variant (Variation ID: 139599). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 01, 2014)	no assertion criteria provided Method: literature only	CILIARY DYSKINESIA, PRIMARY, 29 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000172183.2 First in ClinVar: Jul 11, 2014 Last updated: Jul 11, 2014	Publications: PubMed (1) PubMed: 24747639 Comment on evidence: In 4 affected members of a consanguineous Kuwaiti family with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous 5-bp duplication (c.248_252dupTGCCC) … (more) In 4 affected members of a consanguineous Kuwaiti family with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous 5-bp duplication (c.248_252dupTGCCC) in exon 1 of the CCNO gene, resulting in a frameshift and premature termination (Gly85CysfsTer10). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not present in the 1000 Genomes Project database. One additional patient was found to be compound heterozygous for the c.248_252dupTGCCC mutation and a 2-bp deletion in exon 2 (c.481_482delCT; 607752.0006), resulting in a frameshift and premature termination (Leu161GlyfsTer72). (less)
Likely pathogenic (Aug 01, 2018)	no assertion criteria provided Method: literature only	Primary ciliary dyskinesia Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106485.1 First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 2022	Publications: PubMed (1) PubMed: 30067075

Comment:

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:24747639, PS3_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000139599, PMID:24747639). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000034, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change creates a premature translational stop signal (p.Gly85Cysfs*11) in the CCNO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCNO are known to be pathogenic (PMID: 24747639). This variant is present in population databases (rs753409639, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital mucociliary clearance disorder (PMID: 24747639). ClinVar contains an entry for this variant (Variation ID: 139599). For these reasons, this variant has been classified as 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia.	Shamseldin HE	Human genetics	2020	PMID: 32367404
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
Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.	Wallmeier J	Nature genetics	2014	PMID: 24747639

Text-mined citations for rs587777498 ...

These 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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_021147.5(CCNO):c.248_252dup (p.Gly85fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777498 ...