ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.3101G>A (p.Arg1034His)
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.3101G>A (p.Arg1034His)
Variation ID: 544690 Accession: VCV000544690.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 55719513 (GRCh37) [ NCBI UCSC ] 10: 53959753 (GRCh38) [ 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 28, 2018 May 13, 2023 Jan 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.3101G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Arg1034His missense NM_033056.4:c.3101G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Arg1034His missense NM_001142763.2:c.3116G>A NP_001136235.1:p.Arg1039His missense NM_001142764.2:c.3101G>A NP_001136236.1:p.Arg1034His missense NM_001142765.2:c.2888G>A NP_001136237.1:p.Arg963His missense NM_001142766.2:c.3101G>A NP_001136238.1:p.Arg1034His missense NM_001142767.2:c.2990G>A NP_001136239.1:p.Arg997His missense NM_001142768.2:c.3035G>A NP_001136240.1:p.Arg1012His missense NM_001142769.3:c.3137G>A NP_001136241.1:p.Arg1046His missense NM_001142770.3:c.3101G>A NP_001136242.1:p.Arg1034His missense NM_001142771.2:c.3116G>A NP_001136243.1:p.Arg1039His missense NM_001142772.2:c.3101G>A NP_001136244.1:p.Arg1034His missense NM_001142773.2:c.3035G>A NP_001136245.1:p.Arg1012His missense NM_001354404.2:c.3035G>A NP_001341333.1:p.Arg1012His missense NM_001354411.2:c.3122G>A NP_001341340.1:p.Arg1041His missense NM_001354420.2:c.3101G>A NP_001341349.1:p.Arg1034His missense NM_001354429.2:c.3101G>A NP_001341358.1:p.Arg1034His missense NC_000010.11:g.53959753C>T NC_000010.10:g.55719513C>T NG_009191.3:g.1674430G>A - Protein change
- R1034H, R1012H, R1046H, R963H, R997H, R1039H, R1041H
- Other names
- NM_001384140.1(PCDH15):c.3101G>A
- p.Arg1034His
- Canonical SPDI
- NC_000010.11:53959752: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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
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 |
3325 | 3414 |
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
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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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Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001034599.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 22, 2021 | RCV001580532.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV001580531.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 22, 2022 | RCV002271546.1 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 7, 2022 | RCV001861672.3 |
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
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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 22, 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: SCV001810558.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jul 22, 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: SCV001810559.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jun 22, 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: SCV002556085.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: PCDH15 c.3101G>A (p.Arg1034His) 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.3101G>A (p.Arg1034His) 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 8e-06 in 251362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3101G>A has been reported in the literature in several individuals affected with non-syndromic hearing loss (e.g. Shearer_2013, Bademci_2016, Schrauwen_2018). However, 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 assessments for this variant have been submitted to ClinVar after 2014 and both classified 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
(Sep 07, 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: SCV002220182.2
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 1034 of the PCDH15 protein (p.Arg1034His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1034 of the PCDH15 protein (p.Arg1034His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of nonsyndromic deafness (PMID: 23804846, 26226137, 30029624). This variant is also known as c.3116G>A (p.Arg1039His). ClinVar contains an entry for this variant (Variation ID: 544690). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 Institute Rare Disease Group, Broad Institute
Accession: SCV003761058.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg1034His variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 26226137, 30029624), segregated with disease in 1 affected … (more)
The p.Arg1034His variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 26226137, 30029624), segregated with disease in 1 affected relative from 1 family (PMID: 30029624), and has been identified in 0.005% (1/19946) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs907693214). 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#: 544690) and has been interpreted as likely pathogenic by University of Washington Center for Mendelian Genomics (University of Washington) and as a variant of uncertain significance by Invitae and Genome-Nilou Lab. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Arg1034His variant is pathogenic (PMID: 26226137). 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.Arg1034His variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting, PM3_supporting (Richards 2015). (less)
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Uncertain significance
(Nov 07, 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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GeneDx
Accession: SCV003923785.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 23804846, 26226137, 28483220, 30029624) (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Non-Syndromic Hereditary Hearing Impairment
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001197979.1
First in ClinVar: Apr 15, 2020 Last updated: Apr 15, 2020 |
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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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Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment. | Schrauwen I | BMC medical genetics | 2018 | PMID: 30029624 |
Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort. | Bademci G | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26226137 |
Advancing genetic testing for deafness with genomic technology. | Shearer AE | Journal of medical genetics | 2013 | PMID: 23804846 |
Text-mined citations for rs907693214 ...
HelpRecord last updated Feb 28, 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.