ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.3717+2dup
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.
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001384140.1(PCDH15):c.3717+2dup
Variation ID: 553548 Accession: VCV000553548.15
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 53866639-53866640 (GRCh38) [ NCBI UCSC ] 10: 55626399-55626400 (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 Aug 5, 2018 Jun 17, 2024 Nov 29, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000010.11:53866639:A:AA
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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) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3389 | 3479 |
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
Help
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 24, 2023 | RCV000669022.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2023 | RCV000808578.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV004568520.1 |
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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Uncertain significance
(Aug 29, 2017)
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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: SCV000793718.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Jan 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002818943.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Published functional studies suggest the c.3717+2dupT results in the skipping of exon 27 and utilization of a cryptic splice site (Aparisi et al., 2013); Intronic … (more)
Published functional studies suggest the c.3717+2dupT results in the skipping of exon 27 and utilization of a cryptic splice site (Aparisi et al., 2013); Intronic splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25404053, 22815625, 23451239) (less)
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Likely pathogenic
(Dec 21, 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: SCV002819726.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: PCDH15 c.3717+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: PCDH15 c.3717+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, significantly altering the expected protein size. (Aparisi_2013). The variant allele was found at a frequency of 1.2e-05 in 250884 control chromosomes. c.3717+2dupT has been reported in the literature in individuals affected with Usher Syndrome Type 1F (e.g. Jaijo_2012, Aparisi_2014). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with one lab citing the variant as pathogenic, one as likely pathogenic, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely 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: SCV003761048.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.3717+2dup variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 22815625, 23451239, 25404053) and has been identified in … (more)
The c.3717+2dup variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 22815625, 23451239, 25404053) and has been identified in 0.009% (3/34464) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1248401224). 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#: 553548) and has been interpreted as pathogenic or likely pathogenic by Invitae and Natera, Inc., and as a variant of uncertain significance by Counsyl. Of the 2 affected individuals, 1 of those was a homozygote and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the c.3717+2dup variant is pathogenic (PMID: 22815625, 23451239, 25404053). In vitro functional studies provide some evidence that the c.3717+2dup variant may impact protein function (PMID: 23451239). However, these types of assays may not accurately represent biological function. This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM3, PS3_moderate (Richards 2015). (less)
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Pathogenic
(Aug 10, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000948690.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 27, but is expected to preserve the integrity of the reading-frame (PMID: 23451239). ClinVar contains an entry for this variant (Variation ID: 553548). This variant is also known as c.3717+2dupTT. This variant has been observed in individual(s) with Usher syndrome (PMID: 22815625, 25404053). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change falls in intron 27 of the PCDH15 gene. It does not directly change the encoded amino acid sequence of the PCDH15 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. (less)
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Likely pathogenic
(Nov 29, 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: SCV005055125.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Oct 30, 2020)
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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: SCV002094851.1
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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High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative. | Fuster-García C | Scientific reports | 2018 | PMID: 30459346 |
Targeted next generation sequencing for molecular diagnosis of Usher syndrome. | Aparisi MJ | Orphanet journal of rare diseases | 2014 | PMID: 25404053 |
Study of USH1 splicing variants through minigenes and transcript analysis from nasal epithelial cells. | Aparisi MJ | PloS one | 2013 | PMID: 23451239 |
Mutation screening of the PCDH15 gene in Spanish patients with Usher syndrome type I. | Jaijo T | Molecular vision | 2012 | PMID: 22815625 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs1248401224 ...
HelpRecord last updated Sep 29, 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.