The p.Glu29X (NM_080860.2 c.85G>T) variant in RSPH1 has been previously reported in at least 5 homozygous and 5 compound heterozygous individuals with primary ciliary dyskinesia (Kott 2013, Marshall 2015, Onoufriadis 2014, Knowles 2014). T his variant has been identified in 40/126,700 of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs1383 20978). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a recessive carrier frequency. This non sense variant leads to a premature termination codon at position 29, which is pr edicted to lead to a truncated or absent protein. Biallelic loss of function of the RSPH1 gene has been associated with primary ciliary dyskinesia. In summary, this variant meets criteria to be classified as pathogenic for primary ciliary d yskinesia in an autosomal recessive manner based upon its biallelic occurrence i n individuals with this disease and the predicted impact on the protein. ACMG/AM P criteria applied: PVS1, PM3 (upgraded to Strong based on multiple occurrences) .
ClinVar Genomic variation as it relates to human health
NM_080860.4(RSPH1):c.85G>T (p.Glu29Ter)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_080860.4(RSPH1):c.85G>T (p.Glu29Ter)
Variation ID: 66987 Accession: VCV000066987.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.3 21: 42493049 (GRCh38) [ NCBI UCSC ] 21: 43913159 (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 Sep 29, 2015 Nov 24, 2024 Jan 14, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_080860.4:c.85G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_543136.1:p.Glu29Ter nonsense NM_001286506.2:c.55-186G>T intron variant NC_000021.9:g.42493049C>A NC_000021.8:g.43913159C>A NG_034257.1:g.8306G>T - Protein change
- E29*
- Other names
-
RSPH1, GLU29TER (rs138320978)
p.Glu29*
- Canonical SPDI
- NC_000021.9:42493048:C:A
-
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.
-
0.00040 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00035
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
- 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. |
|||
| LOC126653391 | - | - | - | GRCh38 | - | 82 |
| RSPH1 | - | - |
GRCh38 GRCh37 |
211 | 349 | |
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
|
Apr 4, 2022 | RCV000057509.21 | |
| not provided (1) |
no classification provided
|
- | RCV000190923.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 14, 2024 | RCV000543760.23 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 8, 2023 | RCV004791256.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711668.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Glu29X (NM_080860.2 c.85G>T) variant in RSPH1 has been previously reported in at least 5 homozygous and 5 compound heterozygous individuals with primary ciliary dyskinesia … (more)
The p.Glu29X (NM_080860.2 c.85G>T) variant in RSPH1 has been previously reported in at least 5 homozygous and 5 compound heterozygous individuals with primary ciliary dyskinesia (Kott 2013, Marshall 2015, Onoufriadis 2014, Knowles 2014). T his variant has been identified in 40/126,700 of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs1383 20978). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a recessive carrier frequency. This non sense variant leads to a premature termination codon at position 29, which is pr edicted to lead to a truncated or absent protein. Biallelic loss of function of the RSPH1 gene has been associated with primary ciliary dyskinesia. In summary, this variant meets criteria to be classified as pathogenic for primary ciliary d yskinesia in an autosomal recessive manner based upon its biallelic occurrence i n individuals with this disease and the predicted impact on the protein. ACMG/AM P criteria applied: PVS1, PM3 (upgraded to Strong based on multiple occurrences) . (less)
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Apr 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 24
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002570320.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
This RSPH1 nonsense variant has been identified in multiple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous states. This variant (rs138320978) … (more)
This RSPH1 nonsense variant has been identified in multiple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous states. This variant (rs138320978) is rare (<0.1%) in a large population dataset (gnomAD: 67/282852 total alleles; 0.02369%; no homozygotes) and has been reported in ClinVar (Variation ID: 66987). This nonsense variant results in a premature stop codon in exon 2 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(May 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 24
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512681.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PVS1, PM3 very strong
Geographic origin: Brazil
|
|
|
Pathogenic
(Feb 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 24
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810278.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jun 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 24
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019906.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000624464.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu29*) in the RSPH1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu29*) in the RSPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH1 are known to be pathogenic (PMID: 23993197). This variant is present in population databases (rs138320978, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23993197, 24518672, 24568568, 26139845). ClinVar contains an entry for this variant (Variation ID: 66987). 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
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413388.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PM2, PM3_strong, PS4, PVS1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 05, 2013)
|
no assertion criteria provided
Method: literature only
|
CILIARY DYSKINESIA, PRIMARY, 24, WITHOUT SITUS INVERSUS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000088621.3
First in ClinVar: Oct 20, 2013 Last updated: Feb 12, 2016 |
Comment on evidence:
In a girl of North African descent, born of consanguineous parents, with primary ciliary dyskinesia-24 without situs inversus (CILD24; 615481), Kott et al. (2013) identified … (more)
In a girl of North African descent, born of consanguineous parents, with primary ciliary dyskinesia-24 without situs inversus (CILD24; 615481), Kott et al. (2013) identified a homozygous c.85G-T transversion in exon 2 of the RSPH1 gene, resulting in a glu29-to-ter (E29X) substitution. The mutation was found by homozygosity mapping combined with whole-exome sequencing and confirmed by Sanger sequencing; DNA from the parents was not available. The variant (rs138320978) was found at a low frequency (0.00038) in the Exome Variant Server database, but was not found in homozygous state in 2,276 control individuals. This low frequency was compatible with the expected frequency of a CILD allele. Screening for RSPH1 mutations in 36 additional families with CILD and central complex defects identified another male patient of North African descent who was homozygous for the E29X mutation as well as 3 additional patients of European descent who were compound heterozygous for E29X and another pathogenic mutation in the RSPH1 gene (see, e.g., 609314.0002 and 609324.0005). All patients had early onset of sinopulmonary infections and some had infertility; none had situs inversus. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Kartagener syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000245809.2
First in ClinVar: Sep 29, 2015 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This RSPH1 nonsense variant has been identified in multiple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous states. This variant (rs138320978) is rare (<0.1%) in a large population dataset (gnomAD: 67/282852 total alleles; 0.02369%; no homozygotes) and has been reported in ClinVar (Variation ID: 66987). This nonsense variant results in a premature stop codon in exon 2 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic.
Comment:
ACMG classification criteria: PVS1, PM3 very strong
Comment:
This sequence change creates a premature translational stop signal (p.Glu29*) in the RSPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH1 are known to be pathogenic (PMID: 23993197). This variant is present in population databases (rs138320978, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23993197, 24518672, 24568568, 26139845). ClinVar contains an entry for this variant (Variation ID: 66987). 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:
PM2, PM3_strong, PS4, PVS1
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:
The p.Glu29X (NM_080860.2 c.85G>T) variant in RSPH1 has been previously reported in at least 5 homozygous and 5 compound heterozygous individuals with primary ciliary dyskinesia (Kott 2013, Marshall 2015, Onoufriadis 2014, Knowles 2014). T his variant has been identified in 40/126,700 of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs1383 20978). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a recessive carrier frequency. This non sense variant leads to a premature termination codon at position 29, which is pr edicted to lead to a truncated or absent protein. Biallelic loss of function of the RSPH1 gene has been associated with primary ciliary dyskinesia. In summary, this variant meets criteria to be classified as pathogenic for primary ciliary d yskinesia in an autosomal recessive manner based upon its biallelic occurrence i n individuals with this disease and the predicted impact on the protein. ACMG/AM P criteria applied: PVS1, PM3 (upgraded to Strong based on multiple occurrences) .
Comment:
This RSPH1 nonsense variant has been identified in multiple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous states. This variant (rs138320978) is rare (<0.1%) in a large population dataset (gnomAD: 67/282852 total alleles; 0.02369%; no homozygotes) and has been reported in ClinVar (Variation ID: 66987). This nonsense variant results in a premature stop codon in exon 2 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic.
Comment:
ACMG classification criteria: PVS1, PM3 very strong
Comment:
This sequence change creates a premature translational stop signal (p.Glu29*) in the RSPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH1 are known to be pathogenic (PMID: 23993197). This variant is present in population databases (rs138320978, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23993197, 24518672, 24568568, 26139845). ClinVar contains an entry for this variant (Variation ID: 66987). 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:
PM2, PM3_strong, PS4, PVS1
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 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. | Blanchon S | Journal of medical genetics | 2020 | PMID: 31772028 |
| Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
| Primary Ciliary Dyskinesia. | Adam MP | - | 2019 | PMID: 20301301 |
| Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia. | Marshall CR | G3 (Bethesda, Md.) | 2015 | PMID: 26139845 |
| 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 |
Text-mined citations for rs138320978 ...
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 Nov 25, 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.