ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.2361TGT[2] (p.Val790del)
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.2361TGT[2] (p.Val790del)
Variation ID: 126521 Accession: VCV000126521.15
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 10q21.1 10: 54023049-54023051 (GRCh38) [ NCBI UCSC ] 10: 55782809-55782811 (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 Apr 19, 2014 Jan 6, 2024 Dec 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.2361TGT[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Val790del inframe deletion NM_033056.4:c.2361TGT[2] MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Val790del inframe deletion NM_033056.4:c.2367_2369del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001142763.2:c.2376TGT[2] NP_001136235.1:p.Val795del inframe deletion NM_001142764.2:c.2361TGT[2] NP_001136236.1:p.Val790del inframe deletion NM_001142765.2:c.2148TGT[2] NP_001136237.1:p.Val719del inframe deletion NM_001142766.2:c.2361TGT[2] NP_001136238.1:p.Val790del inframe deletion NM_001142767.2:c.2250TGT[2] NP_001136239.1:p.Val753del inframe deletion NM_001142768.2:c.2295TGT[2] NP_001136240.1:p.Val768del inframe deletion NM_001142769.3:c.2397TGT[2] NP_001136241.1:p.Val802del inframe deletion NM_001142770.3:c.2361TGT[2] NP_001136242.1:p.Val790del inframe deletion NM_001142771.2:c.2376TGT[2] NP_001136243.1:p.Val795del inframe deletion NM_001142772.2:c.2361TGT[2] NP_001136244.1:p.Val790del inframe deletion NM_001142773.2:c.2295TGT[2] NP_001136245.1:p.Val768del inframe deletion NM_001354404.2:c.2295TGT[2] NP_001341333.1:p.Val768del inframe deletion NM_001354411.2:c.2382TGT[2] NP_001341340.1:p.Val797del inframe deletion NM_001354420.2:c.2361TGT[2] NP_001341349.1:p.Val790del inframe deletion NM_001354429.2:c.2361TGT[2] NP_001341358.1:p.Val790del inframe deletion NM_001354430.2:c.2361TGT[2] NP_001341359.1:p.Val790del inframe deletion NC_000010.11:g.54023050CAA[2] NC_000010.10:g.55782810CAA[2] NG_009191.3:g.1611126TGT[2] - Protein change
- V790del, V719del, V753del, V802del, V768del, V795del, V797del
- Other names
- NM_001384140.1(PCDH15):c.2361TGT[2]
- Canonical SPDI
- NC_000010.11:54023048:ACAACAACAA:ACAACAA
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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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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 |
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
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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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Uncertain significance (2) |
criteria provided, single submitter
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Dec 30, 2023 | RCV000114410.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 5, 2022 | RCV000220485.6 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV000675146.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 19, 2022 | RCV002514567.1 |
Submissions - Germline
Classification
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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
(Jul 19, 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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Invitae
Accession: SCV003266889.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This variant, c.2367_2369del, results in the deletion of 1 amino acid(s) of the PCDH15 protein (p.Val790del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.2367_2369del, results in the deletion of 1 amino acid(s) of the PCDH15 protein (p.Val790del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs483352837, gnomAD 0.02%). This variant has been observed in individual(s) with PCDH15-related conditions (PMID: 25930172, 32835555). ClinVar contains an entry for this variant (Variation ID: 126521). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(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: SCV003761068.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Val790del variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 32835555, 25930172) and has been identified in 0.02% … (more)
The p.Val790del variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 32835555, 25930172) and has been identified in 0.02% (3/19950) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs483352837). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 126521) and has been interpreted as pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences) and Institute of Otorhinolaryngology (Sun Yat-sen University) and as a variant of uncertain significance by Counsyl, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Natera, Inc, and Women's Health and Genetics/Laboratory Corporation of America. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Val790del variant is pathogenic (PMID: 25930172). This variant is a deletion of 1 amino acid at position 790 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP Criteria applied: PM4_supporting, PM3_supporting (Richards 2015). (less)
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Uncertain significance
(Apr 05, 2018)
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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: SCV000800745.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Sep 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000272298.4
First in ClinVar: May 29, 2016 Last updated: May 29, 2021 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val790del variant in PCDH15 has been previously reported in the homozygous state in one individual with … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val790del variant in PCDH15 has been previously reported in the homozygous state in one individual with sensorineural hearing loss and segregated in an affected family member. The affected individuals were reported to be age 18 and 28 years, and did not report symptoms of night-blindness. However, electroretinograms were not obtained (Zhan 2015 PMID: 25930172). It has also been identified in one individual with hearing loss by our laboratory who was heterozygous for the variant. This variant has been reported in ClinVar (Variation ID 126521), and it also has been identified in several populations by gnomAD, with the highest frequency of 0.01% (3/19950) of East Asian European chromosomes (http://gnomad.broadinstitute.org). This variant is a deletion of a valine (Val) residue at position 790 and is not predicted to alter the protein reading-frame. It is unclear whether this deletion impacts the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP criteria applied: PM3_Supporting, PM2_Supporting, PP1, PM4_Supporting. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511910.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: PCDH15 c.2367_2369delTGT (p.Val790del) results in an in-frame deletion that is predicted to remove one amino acid from Cadherin-like domain (IPR002126, also known as … (more)
Variant summary: PCDH15 c.2367_2369delTGT (p.Val790del) results in an in-frame deletion that is predicted to remove one amino acid from Cadherin-like domain (IPR002126, also known as EC7 domain (Zhan_2015)) the encoded protein. The variant allele was found at a frequency of 5.6e-05 in 251246 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.2367_2369delTGT has been reported in the literature in one heterozygous individual affected with Usher Syndrome and one homozygous individual affected with non-syndromic hearing loss (Zhan_2015, Zheng_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Dec 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 23
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746395.2
First in ClinVar: Apr 19, 2014 Last updated: Jan 06, 2024 |
Sex: male
Geographic origin: Iran
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Uncertain significance
(Mar 10, 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: SCV002088455.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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pathogenic
(-)
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Flagged submission
flagged submission
Method: not provided
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Deafness, autosomal recessive 23
Affected status: not provided
Allele origin:
biparental
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Institute of Otorhinolaryngology, The First affiliated hospital, Sun Yat-sen University
Accession: SCV000148342.1
First in ClinVar: Apr 19, 2014 Last updated: Apr 19, 2014 |
Comment:
Converted during submission to Pathogenic.
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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A novel missense mutation locus of cadherin 23 and the interaction of cadherin 23 and protocadherin 15 in a patient with usher syndrome. | Zheng C | Ophthalmic genetics | 2020 | PMID: 32835555 |
Beyond Cell-Cell Adhesion: Sensational Cadherins for Hearing and Balance. | Jaiganesh A | Cold Spring Harbor perspectives in biology | 2018 | PMID: 28847902 |
Novel mutation located in EC7 domain of protocadherin-15 uncovered by targeted massively parallel sequencing in a family segregating non-syndromic deafness DFNB23. | Zhan Y | International journal of pediatric otorhinolaryngology | 2015 | PMID: 25930172 |
Text-mined citations for rs483352837 ...
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.