ClinVar Genomic variation as it relates to human health
NM_080860.4(RSPH1):c.275-2A>C
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_080860.4(RSPH1):c.275-2A>C
Variation ID: 66990 Accession: VCV000066990.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 42486463 (GRCh38) [ NCBI UCSC ] 21: 43906573 (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 Mar 16, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_080860.4:c.275-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001286506.2:c.161-2A>C splice acceptor NC_000021.9:g.42486463T>G NC_000021.8:g.43906573T>G NG_034257.1:g.14892A>C NP_543136.1:p.Gly92AlafsTer10 - Protein change
- Other names
- IVS3AS, A-C, -2 (rs151107532)
- Canonical SPDI
- NC_000021.9:42486462:T:G
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00036
The Genome Aggregation Database (gnomAD), exomes 0.00037
The Genome Aggregation Database (gnomAD) 0.00048
Trans-Omics for Precision Medicine (TOPMed) 0.00049
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
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 | ||
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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
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. |
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RSPH1 | - | - |
GRCh38 GRCh37 |
209 | 346 |
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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 20, 2022 | RCV000057512.13 | |
not provided (1) |
no classification provided
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- | RCV000190924.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2024 | RCV000467674.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2018 | RCV000726589.5 | |
RSPH1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV003974945.1 |
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. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: yes
Allele origin:
inherited
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737035.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Comment:
Homozygous, both variants are inherited from each parent. The patient also has an affected sibling carrying the same variants
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Pathogenic
(Nov 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 24
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019905.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 07, 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: SCV000547685.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 3 of the RSPH1 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 3 of the RSPH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs151107532, gnomAD 0.07%). Disruption of this splice site has been observed in individuals with primary ciliary dyskinesia, many of whom were homozygous for this variant (PMID: 23993197, 24518672, 24568568). ClinVar contains an entry for this variant (Variation ID: 66990). Studies have shown that disruption of this splice site results in skipping of exons 4-5 or exons 4-6 and introduces a premature termination codon (PMID: 23993197, 24568568). 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
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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RSPH1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004790655.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The RSPH1 c.275-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the … (more)
The RSPH1 c.275-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous state and compound heterozygous state in multiple unrelated individuals affected with primary ciliary dyskinesia (PCD) (Kott et al. 2013. PubMed ID: 23993197; Knowles et al. 2014. PubMed ID: 24568568; Onoufriadis et al. 2014. PubMed ID: 24518672). In vitro RT-PCR analysis showed that the c.275-2A>C variant leads to the skipping of either exons 4-5 or exons 4-6, resulting in a frameshift and premature protein termination (Kott et al. 2013. PubMed ID: 23993197; Knowles et al. 2014. PubMed ID: 24568568). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in RSPH1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000345709.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Sep 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 24
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003839055.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
This RSPH1 canonical splice variant has been reported in the homozygous or compound heterozygous state in individuals and families with primary ciliary dyskinesia. The variant … (more)
This RSPH1 canonical splice variant has been reported in the homozygous or compound heterozygous state in individuals and families with primary ciliary dyskinesia. The variant (rs151107532) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 67/152098 total alleles; 0.044%; no homozygotes). It has been reported in ClinVar (Variation ID 66990). This variant destroys a canonical splice acceptor site, is predicted to cause abnormal gene splicing, and has supporting functional evidence. We consider c.275-2A>C in RSPH1 to be pathogenic. (less)
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Pathogenic
(Sep 05, 2013)
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no assertion criteria provided
Method: literature only
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CILIARY DYSKINESIA, PRIMARY, 24, WITHOUT SITUS INVERSUS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000088624.3
First in ClinVar: Oct 20, 2013 Last updated: May 01, 2017 |
Comment on evidence:
In 5 patients from 3 European families with primary ciliary dyskinesia without situs inversus (CILD24; 615481), Kott et al. (2013) identified a homozygous A-to-C transversion … (more)
In 5 patients from 3 European families with primary ciliary dyskinesia without situs inversus (CILD24; 615481), Kott et al. (2013) identified a homozygous A-to-C transversion in intron 3 of the RSPH1 gene (c.275-2A-C). RT-PCR showed that the mutation leads to the skipping of exons 4 and 5 and results in premature termination (Gly92AlafsTer10). Another patient was compound heterozygous for this splice site mutation and another pathogenic mutation. The c.275-2A-C mutation was present in dbSNP (rs151107532) and at a low frequency (0.001) in the Exome Variant Server database, which is compatible with the expected frequency of a CILD allele. The homozygous genotype was not found among 2,937 individuals. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Primary ciliary dyskinesia 24
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760472.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 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: SCV000245810.2
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 |
Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects. | Frommer A | American journal of respiratory cell and molecular biology | 2015 | PMID: 25789548 |
Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. | Knowles MR | American journal of respiratory and critical care medicine | 2014 | PMID: 24568568 |
Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects. | Onoufriadis A | Human molecular genetics | 2014 | PMID: 24518672 |
Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. | Kott E | American journal of human genetics | 2013 | PMID: 23993197 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RSPH1 | - | - | - | - |
Text-mined citations for rs151107532 ...
HelpRecord last updated May 19, 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.