ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.2785C>T (p.Arg929Ter)
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_001384140.1(PCDH15):c.2785C>T (p.Arg929Ter)
Variation ID: 370242 Accession: VCV000370242.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 53995732 (GRCh38) [ NCBI UCSC ] 10: 55755492 (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 Jan 6, 2017 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.2785C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Arg929Ter nonsense NM_033056.4:c.2785C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Arg929Ter nonsense NM_001142763.2:c.2800C>T NP_001136235.1:p.Arg934Ter nonsense NM_001142764.2:c.2785C>T NP_001136236.1:p.Arg929Ter nonsense NM_001142765.2:c.2572C>T NP_001136237.1:p.Arg858Ter nonsense NM_001142766.2:c.2785C>T NP_001136238.1:p.Arg929Ter nonsense NM_001142767.2:c.2674C>T NP_001136239.1:p.Arg892Ter nonsense NM_001142768.2:c.2719C>T NP_001136240.1:p.Arg907Ter nonsense NM_001142769.3:c.2821C>T NP_001136241.1:p.Arg941Ter nonsense NM_001142770.3:c.2785C>T NP_001136242.1:p.Arg929Ter nonsense NM_001142771.2:c.2800C>T NP_001136243.1:p.Arg934Ter nonsense NM_001142772.2:c.2785C>T NP_001136244.1:p.Arg929Ter nonsense NM_001142773.2:c.2719C>T NP_001136245.1:p.Arg907Ter nonsense NM_001354404.2:c.2719C>T NP_001341333.1:p.Arg907Ter nonsense NM_001354411.2:c.2806C>T NP_001341340.1:p.Arg936Ter nonsense NM_001354420.2:c.2785C>T NP_001341349.1:p.Arg929Ter nonsense NM_001354429.2:c.2785C>T NP_001341358.1:p.Arg929Ter nonsense NM_001354430.2:c.2785C>T NP_001341359.1:p.Arg929Ter nonsense NC_000010.11:g.53995732G>A NC_000010.10:g.55755492G>A NG_009191.3:g.1638451C>T - Protein change
- R929*, R934*, R858*, R941*, R892*, R907*, R936*
- Other names
- NM_001384140.1(PCDH15):c.2785C>T
- p.Arg929Ter
- Canonical SPDI
- NC_000010.11:53995731:G:A
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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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PCDH15 | - | - |
GRCh38 GRCh37 |
3333 | 3421 |
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
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
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV000412338.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000811416.6 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 10, 2023 | RCV000770852.2 |
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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Pathogenic
(Nov 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1F
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361472.2
First in ClinVar: Jun 22, 2020 Last updated: Dec 24, 2022 |
Comment:
Variant summary: PCDH15 c.2785C>T (p.Arg929X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PCDH15 c.2785C>T (p.Arg929X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250804 control chromosomes. c.2785C>T has been reported in the literature in individuals affected with Usher Syndrome Type 1F (Ouyang_2005, Zein_2014, Sethna_2021), and was also identified in a carrier screening study (Perreault-Micale_2014). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1F
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000485499.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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Usher syndrome type 1F
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761061.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg929Ter variant in PCDH15 has been reported in 4 individuals with Usher syndrome type 1F (PMID: 15660226, 25307757, 25425308) and has been identified in … (more)
The p.Arg929Ter variant in PCDH15 has been reported in 4 individuals with Usher syndrome type 1F (PMID: 15660226, 25307757, 25425308) and has been identified in 0.003% (1/34576) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1057516342). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 370242) and has been interpreted as pathogenic or likely pathogenic by Counsyl, Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Genetic Testing Center for Deafness (Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital). Of the 4 affected individuals, 2 were a compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg929Ter variant is pathogenic (VariationID: 4933; PMID: 25425308). This nonsense variant leads to a premature termination codon at position 929, which is predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). (less)
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Pathogenic
(Mar 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 23
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004200839.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 18, 2024)
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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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Invitae
Accession: SCV000951682.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg929*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg929*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 15660226, 25307757, 25425308). ClinVar contains an entry for this variant (Variation ID: 370242). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 26, 2019)
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no assertion criteria provided
Method: case-control
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Autosomal recessive nonsyndromic hearing loss 23
Affected status: yes
Allele origin:
inherited
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000902354.1
First in ClinVar: May 12, 2019 Last updated: May 12, 2019 |
Number of individuals with the variant: 1
Clinical Features:
hearing loss (present)
Family history: yes
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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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Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome. | Sethna S | eLife | 2021 | PMID: 34751129 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Cone responses in Usher syndrome types 1 and 2 by microvolt electroretinography. | Zein WM | Investigative ophthalmology & visual science | 2014 | PMID: 25425308 |
Truncating variants in the majority of the cytoplasmic domain of PCDH15 are unlikely to cause Usher syndrome 1F. | Perreault-Micale C | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25307757 |
Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. | Ouyang XM | Human genetics | 2005 | PMID: 15660226 |
PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. | Ahmed ZM | Human molecular genetics | 2003 | PMID: 14570705 |
Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. | Alagramam KN | Human molecular genetics | 2001 | PMID: 11487575 |
Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. | Ahmed ZM | American journal of human genetics | 2001 | PMID: 11398101 |
Text-mined citations for rs1057516342 ...
HelpRecord last updated Mar 30, 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.