ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.3761dup (p.Asn1254fs)
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.3761dup (p.Asn1254fs)
Variation ID: 2412658 Accession: VCV002412658.2
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 53857219-53857220 (GRCh38) [ NCBI UCSC ] 10: 55616979-55616980 (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 Feb 8, 2023 Feb 20, 2024 Apr 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.3761dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Asn1254fs frameshift NM_033056.4:c.3761dup MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Asn1254fs frameshift NM_001142763.2:c.3776dup NP_001136235.1:p.Asn1259fs frameshift NM_001142764.2:c.3761dup NP_001136236.1:p.Asn1254fs frameshift NM_001142765.2:c.3548dup NP_001136237.1:p.Asn1183fs frameshift NM_001142766.2:c.3761dup NP_001136238.1:p.Asn1254fs frameshift NM_001142767.2:c.3650dup NP_001136239.1:p.Asn1217fs frameshift NM_001142768.2:c.3695dup NP_001136240.1:p.Asn1232fs frameshift NM_001142769.3:c.3797dup NP_001136241.1:p.Asn1266fs frameshift NM_001142770.3:c.3761dup NP_001136242.1:p.Asn1254fs frameshift NM_001142771.2:c.3776dup NP_001136243.1:p.Asn1259fs frameshift NM_001142772.2:c.3761dup NP_001136244.1:p.Asn1254fs frameshift NM_001142773.2:c.3695dup NP_001136245.1:p.Asn1232fs frameshift NM_001354404.2:c.3695dup NP_001341333.1:p.Asn1232fs frameshift NM_001354411.2:c.3782dup NP_001341340.1:p.Asn1261fs frameshift NM_001354420.2:c.3761dup NP_001341349.1:p.Asn1254fs frameshift NM_001354429.2:c.3761dup NP_001341358.1:p.Asn1254fs frameshift NC_000010.11:g.53857221dup NC_000010.10:g.55616981dup NG_009191.3:g.1776963dup - Protein change
- N1259fs, N1261fs, N1217fs, N1254fs, N1183fs, N1232fs, N1266fs
- Other names
- NM_001384140.1:c.3761dup
- Canonical SPDI
- NC_000010.11:53857219:TT:TTT
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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.
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- 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 | ||
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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 |
3320 | 3407 |
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 (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002789950.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2023 | RCV003720761.1 |
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
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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
(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: SCV003761046.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Asn1254fs variant in PCDH15 has been reported in 1 individual, in the homozygous state, with Usher syndrome type 1F (PMID: 35779349), and has been … (more)
The p.Asn1254fs variant in PCDH15 has been reported in 1 individual, in the homozygous state, with Usher syndrome type 1F (PMID: 35779349), and has been identified in 0.005% (6/113622) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs762129852). 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 is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1254 and leads to a premature termination codon 54 amino acids downstream. This alteration is then 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
(Apr 28, 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: SCV004502054.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2412658). This variant has not been … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2412658). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. This variant is present in population databases (rs762129852, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Asn1254Lysfs*54) 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). (less)
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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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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 this variant ...
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.