VCV001725956.5 - ClinVar

NM_001384140.1(PCDH15):c.251G>A (p.Trp84Ter)

Germline

Classification

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.

(2)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001384140.1(PCDH15):c.251G>A (p.Trp84Ter)

Variation ID: 1725956 Accession: VCV001725956.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q21.1 10: 54378849 (GRCh38) [ NCBI UCSC ] 10: 56138609 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 19, 2022	Feb 20, 2024	Aug 29, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001384140.1:c.251G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001371069.1:p.Trp84Ter	nonsense
NM_033056.4:c.251G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_149045.3:p.Trp84Ter	nonsense
NM_001142763.2:c.266G>A	NP_001136235.1:p.Trp89Ter	nonsense
NM_001142764.2:c.251G>A	NP_001136236.1:p.Trp84Ter	nonsense
NM_001142765.2:c.251G>A	NP_001136237.1:p.Trp84Ter	nonsense
NM_001142766.2:c.251G>A	NP_001136238.1:p.Trp84Ter	nonsense
NM_001142767.2:c.251G>A	NP_001136239.1:p.Trp84Ter	nonsense
NM_001142768.2:c.185G>A	NP_001136240.1:p.Trp62Ter	nonsense
NM_001142769.3:c.266G>A	NP_001136241.1:p.Trp89Ter	nonsense
NM_001142770.3:c.251G>A	NP_001136242.1:p.Trp84Ter	nonsense
NM_001142771.2:c.266G>A	NP_001136243.1:p.Trp89Ter	nonsense
NM_001142772.2:c.251G>A	NP_001136244.1:p.Trp84Ter	nonsense
NM_001142773.2:c.185G>A	NP_001136245.1:p.Trp62Ter	nonsense
NM_001354404.2:c.185G>A	NP_001341333.1:p.Trp62Ter	nonsense
NM_001354411.2:c.251G>A	NP_001341340.1:p.Trp84Ter	nonsense
NM_001354420.2:c.251G>A	NP_001341349.1:p.Trp84Ter	nonsense
NM_001354429.2:c.251G>A	NP_001341358.1:p.Trp84Ter	nonsense
NM_001354430.2:c.251G>A	NP_001341359.1:p.Trp84Ter	nonsense
NC_000010.11:g.54378849C>T
NC_000010.10:g.56138609C>T
NG_009191.3:g.1255334G>A

... more HGVS ... less HGVS

Protein change

W62*, W84*, W89*

Other names

Canonical SPDI

NC_000010.11:54378848:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

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
Gene	OMIM	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.
PCDH15		-	-	GRCh38 GRCh37	3392	3482

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.
Usher syndrome type 1D	Likely pathogenic (1)	criteria provided, single submitter	Apr 23, 2022	RCV002306927.2
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 29, 2022	RCV003099158.3

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 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.
Likely pathogenic (Apr 23, 2022)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Usher syndrome type 1D Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV002604022.2 First in ClinVar: Nov 19, 2022 Last updated: Dec 24, 2022	Comment: NM_033056.3(PCDH15):c.251G>A(W84) is expected to be pathogenic in the context of PCDH15-related disorders. This variant is predicted to lead to an abnormal or absent protein product … (more) NM_033056.3(PCDH15):c.251G>A(W84) is expected to be pathogenic in the context of PCDH15-related disorders. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in PCDH15, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Aug 29, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003325434.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 11398101‚ 11487575‚ 14570705 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp84*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). (less)

Comment:

NM_033056.3(PCDH15):c.251G>A(W84*) is expected to be pathogenic in the context of PCDH15-related disorders. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in PCDH15, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp84*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705).

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23.	Ahmed ZM	Human molecular genetics	2003	PMID: 14570705
Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F.	Alagramam KN	Human molecular genetics	2001	PMID: 11487575
Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F.	Ahmed ZM	American journal of human genetics	2001	PMID: 11398101

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001384140.1(PCDH15):c.251G>A (p.Trp84Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...