ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.131T>C (p.Val44Ala)
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.
Pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001384140.1(PCDH15):c.131T>C (p.Val44Ala)
Variation ID: 450626 Accession: VCV000450626.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 54527838 (GRCh38) [ NCBI UCSC ] 10: 56287598 (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 19, 2017 Mar 26, 2023 Jan 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.131T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Val44Ala missense NM_033056.4:c.131T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Val44Ala missense NM_001142763.2:c.146T>C NP_001136235.1:p.Val49Ala missense NM_001142764.2:c.131T>C NP_001136236.1:p.Val44Ala missense NM_001142765.2:c.131T>C NP_001136237.1:p.Val44Ala missense NM_001142766.2:c.131T>C NP_001136238.1:p.Val44Ala missense NM_001142767.2:c.131T>C NP_001136239.1:p.Val44Ala missense NM_001142768.2:c.91+136334T>C intron variant NM_001142769.3:c.146T>C NP_001136241.1:p.Val49Ala missense NM_001142770.3:c.131T>C NP_001136242.1:p.Val44Ala missense NM_001142771.2:c.146T>C NP_001136243.1:p.Val49Ala missense NM_001142772.2:c.131T>C NP_001136244.1:p.Val44Ala missense NM_001142773.2:c.91+136334T>C intron variant NM_001354404.2:c.91+136334T>C intron variant NM_001354411.2:c.131T>C NP_001341340.1:p.Val44Ala missense NM_001354420.2:c.131T>C NP_001341349.1:p.Val44Ala missense NM_001354429.2:c.131T>C NP_001341358.1:p.Val44Ala missense NM_001354430.2:c.131T>C NP_001341359.1:p.Val44Ala missense NC_000010.11:g.54527838A>G NC_000010.10:g.56287598A>G NG_009191.3:g.1106345T>C - Protein change
- V44A, V49A
- Other names
- NM_001384140.1(PCDH15):c.131T>C
- p.Val44Ala
- Canonical SPDI
- NC_000010.11:54527837:A:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00006
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
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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LOC105378311 | - | - | - | GRCh38 | - | 65 |
PCDH15 | - | - |
GRCh38 GRCh37 |
3319 | 3406 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Sep 17, 2022 | RCV000522599.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 7, 2018 | RCV001004802.1 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV001275408.5 |
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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Pathogenic
(May 07, 2018)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 23
Affected status: yes
Allele origin:
germline
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Laboratory of Prof. Karen Avraham, Tel Aviv University
Accession: SCV001164290.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
Recessive, congenital, profound NSHL
Ethnicity/Population group: Jewish Iraqi
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Uncertain significance
(May 18, 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: SCV001653364.1
First in ClinVar: Jun 03, 2021 Last updated: Jun 03, 2021 |
Sex: mixed
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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: SCV003761096.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Val44Ala variant in PCDH15 has been reported in 1 individual, in the homozygous state, with Usher syndrome type 1F (PMID: 33111345), and has been … (more)
The p.Val44Ala variant in PCDH15 has been reported in 1 individual, in the homozygous state, with Usher syndrome type 1F (PMID: 33111345), and has been identified in 0.007% (2/30514) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750302536). 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#: 450626) and has been interpreted as pathogenic by Laboratory of Prof. Karen Avraham (Tel Aviv University) and as a variant of uncertain significance by Invitae, GeneDx, Natera, Inc., and Genome-Nilou Lab. 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.Val44Ala variant is uncertain. ACMG/AMP Criteria applied: BP4, PM3_supporting, PM2_supporting (Richards 2015). (less)
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Uncertain significance
(Apr 07, 2020)
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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: SCV000619232.3
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33111345) (less)
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Uncertain significance
(Sep 17, 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: SCV001487685.2
First in ClinVar: Mar 07, 2021 Last updated: Mar 26, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 44 of the PCDH15 protein (p.Val44Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 44 of the PCDH15 protein (p.Val44Ala). This variant is present in population databases (rs750302536, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 33111345). This variant is also known as NM_001142769.1:c.146T>C Val49Ala. ClinVar contains an entry for this variant (Variation ID: 450626). 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
(Apr 15, 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: SCV001460558.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1. | Brownstein Z | Clinical genetics | 2020 | PMID: 33111345 |
Text-mined citations for rs750302536 ...
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.