ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.2581G>A (p.Val861Met)
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.2581G>A (p.Val861Met)
Variation ID: 300188 Accession: VCV000300188.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 54020362 (GRCh38) [ NCBI UCSC ] 10: 55780122 (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 Dec 6, 2016 Feb 7, 2023 Sep 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.2581G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Val861Met missense NM_033056.4:c.2581G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Val861Met missense NM_001142763.2:c.2596G>A NP_001136235.1:p.Val866Met missense NM_001142764.2:c.2581G>A NP_001136236.1:p.Val861Met missense NM_001142765.2:c.2368G>A NP_001136237.1:p.Val790Met missense NM_001142766.2:c.2581G>A NP_001136238.1:p.Val861Met missense NM_001142767.2:c.2470G>A NP_001136239.1:p.Val824Met missense NM_001142768.2:c.2515G>A NP_001136240.1:p.Val839Met missense NM_001142769.3:c.2617G>A NP_001136241.1:p.Val873Met missense NM_001142770.3:c.2581G>A NP_001136242.1:p.Val861Met missense NM_001142771.2:c.2596G>A NP_001136243.1:p.Val866Met missense NM_001142772.2:c.2581G>A NP_001136244.1:p.Val861Met missense NM_001142773.2:c.2515G>A NP_001136245.1:p.Val839Met missense NM_001354404.2:c.2515G>A NP_001341333.1:p.Val839Met missense NM_001354411.2:c.2602G>A NP_001341340.1:p.Val868Met missense NM_001354420.2:c.2581G>A NP_001341349.1:p.Val861Met missense NM_001354429.2:c.2581G>A NP_001341358.1:p.Val861Met missense NM_001354430.2:c.2581G>A NP_001341359.1:p.Val861Met missense NC_000010.11:g.54020362C>T NC_000010.10:g.55780122C>T NG_009191.3:g.1613821G>A - Protein change
- V861M, V790M, V824M, V873M, V868M, V866M, V839M
- Other names
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- Canonical SPDI
- NC_000010.11:54020361:C:T
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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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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00051
Exome Aggregation Consortium (ExAC) 0.00058
The Genome Aggregation Database (gnomAD), exomes 0.00068
Trans-Omics for Precision Medicine (TOPMed) 0.00079
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000322580.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763656.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 24, 2017 | RCV000614926.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 12, 2021 | RCV001375215.2 | |
Uncertain significance (3) |
criteria provided, single submitter
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Sep 13, 2022 | RCV001246481.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 14, 2021 | RCV001578639.2 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jul 14, 2021 | RCV001578640.4 |
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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Uncertain significance
(Oct 31, 2018)
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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: SCV000894536.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Aug 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711187.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Val861Met variant in PCDH15 has been reported in the heterozygous state in one individual with Usher syndrome who did not carry a variant on … (more)
The p.Val861Met variant in PCDH15 has been reported in the heterozygous state in one individual with Usher syndrome who did not carry a variant on the other all ele (Bujakowska 2014). It has also been identified in 0.09% (111/126546) of Euro pean chromosomes and 0.13% (46/34366) of Latino chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142512524); th ough this frequency is not high enough to rule out a pathogenic role. Computatio nal prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of t he p.Val861Met variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000363189.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001571917.2
First in ClinVar: Apr 29, 2021 Last updated: Apr 29, 2021 |
Comment:
PM2_Supporting
Testing laboratory: CeGaT Praxis fuer Humangenetik Tuebingen
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Uncertain significance
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1F
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001805902.1
First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
Sex: mixed
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Uncertain significance
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 23
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001805901.1
First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
Sex: mixed
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Uncertain significance
(Sep 13, 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: SCV001419839.2
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 861 of the PCDH15 protein (p.Val861Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 861 of the PCDH15 protein (p.Val861Met). This variant is present in population databases (rs142512524, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Usher syndrome (PMID: 25468891). ClinVar contains an entry for this variant (Variation ID: 300188). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH15 protein function. 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
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921524.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975540.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Jan 19, 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: SCV002086643.1
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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Targeted exon sequencing in Usher syndrome type I. | Bujakowska KM | Investigative ophthalmology & visual science | 2014 | PMID: 25468891 |
Text-mined citations for rs142512524 ...
HelpRecord last updated Dec 25, 2023
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.