ClinVar Genomic variation as it relates to human health
NM_033056.4(PCDH15):c.4812G>T (p.Arg1604Ser)
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_033056.4(PCDH15):c.4812G>T (p.Arg1604Ser)
Variation ID: 227009 Accession: VCV000227009.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 53822914 (GRCh38) [ NCBI UCSC ] 10: 55582674 (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 May 29, 2016 Apr 15, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.4368-2684G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_033056.4:c.4812G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Arg1604Ser missense NM_001142763.2:c.4833G>T NP_001136235.1:p.Arg1611Ser missense NM_001142764.2:c.4818G>T NP_001136236.1:p.Arg1606Ser missense NM_001142765.2:c.4605G>T NP_001136237.1:p.Arg1535Ser missense NM_001142766.2:c.4803G>T NP_001136238.1:p.Arg1601Ser missense NM_001142767.2:c.4692G>T NP_001136239.1:p.Arg1564Ser missense NM_001142768.2:c.4752G>T NP_001136240.1:p.Arg1584Ser missense NM_001142769.3:c.4409+2222G>T intron variant NM_001142770.3:c.4373+2222G>T intron variant NM_001142771.2:c.4388+2222G>T intron variant NM_001142772.2:c.4373+2222G>T intron variant NM_001142773.2:c.4743G>T NP_001136245.1:p.Arg1581Ser missense NM_001354404.2:c.4746G>T NP_001341333.1:p.Arg1582Ser missense NM_001354411.2:c.4388+4479G>T intron variant NM_001354420.2:c.4367+4479G>T intron variant NM_001354429.2:c.4367+4479G>T intron variant NC_000010.11:g.53822914C>A NC_000010.10:g.55582674C>A NG_009191.3:g.1811269G>T - Protein change
- R1604S, R1535S, R1584S, R1601S, R1564S, R1582S, R1606S, R1581S, R1611S
- Other names
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- Canonical SPDI
- NC_000010.11:53822913:C: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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0.00459 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00066
Trans-Omics for Precision Medicine (TOPMed) 0.00129
1000 Genomes Project 30x 0.00375
1000 Genomes Project 0.00459
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 |
3333 | 3421 |
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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Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2023 | RCV000215424.5 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000287812.5 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000839178.15 | |
Benign (1) |
no assertion criteria provided
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Jan 6, 2020 | RCV001272402.1 | |
Uncertain significance (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV001822855.1 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 29, 2022 | RCV002500691.1 |
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
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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Benign
(Oct 20, 2015)
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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: SCV000269625.3
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
p.Arg1604Ser in exon 33 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 2.75% (238/8654) of East … (more)
p.Arg1604Ser in exon 33 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 2.75% (238/8654) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; rs148718874). (less)
Number of individuals with the variant: 2
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Likely benign
(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: SCV000363137.3
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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Likely benign
(Apr 29, 2022)
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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: SCV002810226.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(May 23, 2019)
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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: SCV000981062.3
First in ClinVar: Aug 26, 2019 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26166082, 29625443, 31180159, 33090715)
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Likely benign
(Jun 28, 2023)
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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: SCV004021255.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: PCDH15 c.4812G>T (p.Arg1604Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: PCDH15 c.4812G>T (p.Arg1604Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251356 control chromosomes, predominantly at a frequency of 0.028 within the East Asian subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.4812G>T has been reported in the literature in individuals affected with poor cochlear implants outcome and vestibular dysfunction (examples: Wu_2015 and Guan_2021) and one of these reports classified the variant as VUS (Guan_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. The following publications have been ascertained in the context of this evaluation (PMID: 26166082, 34416374). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and benign/ likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Benign
(Jan 30, 2024)
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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: SCV001055465.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Benign
(Dec 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004125391.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
PCDH15: BP4, BS1, BS2
Number of individuals with the variant: 1
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Benign
(Jan 06, 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: SCV001454387.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(Jul 01, 2021)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 23
Affected status: yes
Allele origin:
inherited
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WangQJ Lab, Chinese People's Liberation Army General Hospital
Accession: SCV001762502.1
First in ClinVar: Feb 02, 2022 Last updated: Feb 02, 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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Family trio-based sequencing in 404 sporadic bilateral hearing loss patients discovers recessive and De novo genetic variants in multiple ways. | Guan J | European journal of medical genetics | 2021 | PMID: 34416374 |
Identifying Children With Poor Cochlear Implantation Outcomes Using Massively Parallel Sequencing. | Wu CC | Medicine | 2015 | PMID: 26166082 |
Text-mined citations for rs148718874 ...
HelpRecord last updated Apr 15, 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.