ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.3316C>T (p.Arg1106Ter)
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.3316C>T (p.Arg1106Ter)
Variation ID: 46464 Accession: VCV000046464.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 53938872 (GRCh38) [ NCBI UCSC ] 10: 55698632 (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 Mar 29, 2015 Apr 6, 2024 Feb 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.3316C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Arg1106Ter nonsense NM_033056.4:c.3316C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Arg1106Ter nonsense NM_001142763.2:c.3331C>T NP_001136235.1:p.Arg1111Ter nonsense NM_001142764.2:c.3316C>T NP_001136236.1:p.Arg1106Ter nonsense NM_001142765.2:c.3103C>T NP_001136237.1:p.Arg1035Ter nonsense NM_001142766.2:c.3316C>T NP_001136238.1:p.Arg1106Ter nonsense NM_001142767.2:c.3205C>T NP_001136239.1:p.Arg1069Ter nonsense NM_001142768.2:c.3250C>T NP_001136240.1:p.Arg1084Ter nonsense NM_001142769.3:c.3352C>T NP_001136241.1:p.Arg1118Ter nonsense NM_001142770.3:c.3316C>T NP_001136242.1:p.Arg1106Ter nonsense NM_001142771.2:c.3331C>T NP_001136243.1:p.Arg1111Ter nonsense NM_001142772.2:c.3316C>T NP_001136244.1:p.Arg1106Ter nonsense NM_001142773.2:c.3250C>T NP_001136245.1:p.Arg1084Ter nonsense NM_001354404.2:c.3250C>T NP_001341333.1:p.Arg1084Ter nonsense NM_001354411.2:c.3337C>T NP_001341340.1:p.Arg1113Ter nonsense NM_001354420.2:c.3316C>T NP_001341349.1:p.Arg1106Ter nonsense NM_001354429.2:c.3316C>T NP_001341358.1:p.Arg1106Ter nonsense NC_000010.11:g.53938872G>A NC_000010.10:g.55698632G>A NG_009191.3:g.1695311C>T - Protein change
- R1106*, R1084*, R1118*, R1069*, R1035*, R1111*, R1113*
- Other names
- NM_001384140.1(PCDH15):c.3316C>T
- p.Arg1106Ter
- Canonical SPDI
- NC_000010.11:53938871: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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PCDH15 | - | - |
GRCh38 GRCh37 |
3320 | 3407 |
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
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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 | RCV000039723.19 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515240.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2017 | RCV000824731.11 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2023 | RCV001386496.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2022 | RCV003389450.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 11, 2024 | RCV003473289.3 |
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. |
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Pathogenic
(Aug 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000063412.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Arg1106X variant in PCDH15 has been reported in the homozygous state in on e individual with Usher syndrome type I (Ammar-Khodja 2009). It has … (more)
The p.Arg1106X variant in PCDH15 has been reported in the homozygous state in on e individual with Usher syndrome type I (Ammar-Khodja 2009). It has also been id entified in 5/111450 European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org; dbSNP rs202033121). Although this varian t has been seen in the general population, its frequency is low enough to be con sistent with a recessive carrier frequency. The p.Arg1106X variant leads to a pr emature stop codon at position 1106, which is predicted to lead to a truncated o r absent protein. In summary, this variant meets criteria to be classified as pa thogenic for autosomal recessive Usher syndrome based on the previously reported individual, low frequency in the general population, and predicted loss of func tion of the protein. (less)
Number of individuals with the variant: 3
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Likely pathogenic
(Aug 20, 2014)
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criteria provided, single submitter
Method: literature only
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Usher syndrome, type 1F
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220613.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Dec 31, 2022)
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criteria provided, single submitter
Method: research
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Usher syndrome
Affected status: yes
Allele origin:
unknown
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SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation
Accession: SCV003927118.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Number of individuals with the variant: 1
Comment on evidence:
This variant was observed in digenic inheritance with the variant NC_000001.10:g.216371836C>A.
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Pathogenic
(Oct 18, 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: SCV004200771.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Mar 30, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003808722.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 25, 2023)
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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: SCV001586740.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1106*) 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.Arg1106*) 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 (rs202033121, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 18484607, 19375528). ClinVar contains an entry for this variant (Variation ID: 46464). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1D
Usher syndrome type 1F Autosomal recessive nonsyndromic hearing loss 23
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611293.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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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: SCV003761054.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg1106Ter variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 19375528, 18484607) and has been identified in 0.004% … (more)
The p.Arg1106Ter variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 19375528, 18484607) and has been identified in 0.004% (5/113538) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs202033121). 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#: 46464) and has been interpreted as pathogenic or likely pathogenic by Fulgent Genetics, Counsyl, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Invitae, and Natera, Inc.. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Arg1106Ter variant is pathogenic (PMID: 19375528). This nonsense variant leads to a premature termination codon at position 1106, 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, PM2_supporting, PM3_supporting (Richards 2015). (less)
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Pathogenic
(Feb 11, 2024)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 23
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801128.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Oct 15, 2021)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 1F
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002092957.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Molecular screening of deafness in Algeria: high genetic heterogeneity involving DFNB1 and the Usher loci, DFNB2/USH1B, DFNB12/USH1D and DFNB23/USH1F. | Ammar-Khodja F | European journal of medical genetics | 2009 | PMID: 19375528 |
UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes. | Baux D | Human mutation | 2008 | PMID: 18484607 |
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 rs202033121 ...
HelpRecord last updated Apr 06, 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.