ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.833G>A (p.Arg278His)
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.833G>A (p.Arg278His)
Variation ID: 523753 Accession: VCV000523753.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 54317314 (GRCh38) [ NCBI UCSC ] 10: 56077074 (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 31, 2020 Feb 7, 2023 Jan 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.833G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Arg278His missense NM_033056.4:c.833G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Arg278His missense NM_001142763.2:c.848G>A NP_001136235.1:p.Arg283His missense NM_001142764.2:c.833G>A NP_001136236.1:p.Arg278His missense NM_001142765.2:c.833G>A NP_001136237.1:p.Arg278His missense NM_001142766.2:c.833G>A NP_001136238.1:p.Arg278His missense NM_001142767.2:c.722G>A NP_001136239.1:p.Arg241His missense NM_001142768.2:c.767G>A NP_001136240.1:p.Arg256His missense NM_001142769.3:c.848G>A NP_001136241.1:p.Arg283His missense NM_001142770.3:c.833G>A NP_001136242.1:p.Arg278His missense NM_001142771.2:c.848G>A NP_001136243.1:p.Arg283His missense NM_001142772.2:c.833G>A NP_001136244.1:p.Arg278His missense NM_001142773.2:c.767G>A NP_001136245.1:p.Arg256His missense NM_001354404.2:c.767G>A NP_001341333.1:p.Arg256His missense NM_001354411.2:c.833G>A NP_001341340.1:p.Arg278His missense NM_001354420.2:c.833G>A NP_001341349.1:p.Arg278His missense NM_001354429.2:c.833G>A NP_001341358.1:p.Arg278His missense NM_001354430.2:c.833G>A NP_001341359.1:p.Arg278His missense NC_000010.11:g.54317314C>T NC_000010.10:g.56077074C>T NG_009191.3:g.1316869G>A - Protein change
- R278H, R283H, R241H, R256H
- Other names
- NM_001384140.1(PCDH15):c.833G>A
- p.Arg278His
- Canonical SPDI
- NC_000010.11:54317313: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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- 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
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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 |
3319 | 3406 |
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 (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001106210.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 1, 2022 | RCV001860486.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002265826.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002529805.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 30, 2021 | RCV002483762.1 |
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
(Apr 27, 2017)
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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: SCV001263250.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(May 04, 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: SCV002547619.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
Variant summary: PCDH15 c.833G>A (p.Arg278His) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of … (more)
Variant summary: PCDH15 c.833G>A (p.Arg278His) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251632 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.833G>A has been reported in the literature in individuals with hearing loss (Miyagawa_2013, Mutai_2013). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 30, 2021)
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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: SCV002791268.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Nov 01, 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: SCV002291211.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 278 of the PCDH15 protein (p.Arg278His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 278 of the PCDH15 protein (p.Arg278His). This variant is present in population databases (rs369442293, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 523753). 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
(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: SCV003761086.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg278His variant in PCDH15 has been reported in 3 individuals with Usher syndrome type 1F (PMID: 23967202, 30245029, 24164807), segregated with disease in 2 … (more)
The p.Arg278His variant in PCDH15 has been reported in 3 individuals with Usher syndrome type 1F (PMID: 23967202, 30245029, 24164807), segregated with disease in 2 affected relatives from 1 family (PMID: 24164807) and has been identified in 0.01% (3/24966) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs369442293). 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#: 523753) and has been interpreted as a variant of uncertain significance by Invitae and Illumina Laboratory Services. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg278His variant is pathogenic (VariationID: 4928; PMID: 24164807). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg278His variant is uncertain. ACMG/AMP Criteria applied: PM3, BP4, PP1 (Richards 2015). (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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Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. | Azaiez H | American journal of human genetics | 2018 | PMID: 30245029 |
Beyond Cell-Cell Adhesion: Sensational Cadherins for Hearing and Balance. | Jaiganesh A | Cold Spring Harbor perspectives in biology | 2018 | PMID: 28847902 |
Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study. | Mutai H | Orphanet journal of rare diseases | 2013 | PMID: 24164807 |
Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients. | Miyagawa M | PloS one | 2013 | PMID: 23967202 |
Text-mined citations for rs369442293 ...
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.