VCV003075985.1 - ClinVar

NM_016580.4(PCDH12):c.954C>A (p.Tyr318Ter)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016580.4(PCDH12):c.954C>A (p.Tyr318Ter)

Variation ID: 3075985 Accession: VCV003075985.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.3 5: 141956898 (GRCh38) [ NCBI UCSC ] 5: 141336463 (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	Apr 20, 2024	Apr 20, 2024	Mar 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016580.4:c.954C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057664.1:p.Tyr318Ter	nonsense
NC_000005.10:g.141956898G>T
NC_000005.9:g.141336463G>T

Protein change

Y318*

Other names

Canonical SPDI

NC_000005.10:141956897:G: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.
PCDH12		-	-	GRCh38 GRCh37	78	425
RNF14		-	-	GRCh38 GRCh37	21	368

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.
Diencephalic-mesencephalic junction dysplasia	Likely pathogenic (1)	criteria provided, single submitter	Mar 20, 2024	RCV004018303.1

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.
Likely Pathogenic (Mar 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Diencephalic-mesencephalic junction dysplasia (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847462.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (4) PubMed: 27164683‚ 30178464‚ 34773825‚ 37480564 Comment: The p.Tyr318X variant in PCDH12 has not been previously reported in individuals with PCDH12-associated disorders but has been identified in 0.0058% (4/68016) of European chromosomes … (more) The p.Tyr318X variant in PCDH12 has not been previously reported in individuals with PCDH12-associated disorders but has been identified in 0.0058% (4/68016) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 318, which is predicted to lead to a truncated or absent protein. Loss of function variants in the PCDH12 gene have been observed in many individuals with autosomal recessive diencephalic mesencephalic junction dysplasia syndrome (Aran 2016 PMID: 27164683, Guemez-Gamboa 2018 PMID: 30178464, Fazeli 2021 PMID: 34773825). Additionally, ex vivo functional studies using a cortical organoid model from human stem cell line knockouts that were missing the PCDH12 protein have shown that loss of PCDH12 severely impairs cerebral organoid development with reduced proliferative areas and disrupted laminar organization (Rakotomamonjy 2023 PMID: 37480564), which is in line with the clinical phenotype observed in patients. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive diencephalic mesencephalic junction dysplasia syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. (less)

Comment:

The p.Tyr318X variant in PCDH12 has not been previously reported in individuals with PCDH12-associated disorders but has been identified in 0.0058% (4/68016) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 318, which is predicted to lead to a truncated or absent protein. Loss of function variants in the PCDH12 gene have been observed in many individuals with autosomal recessive diencephalic mesencephalic junction dysplasia syndrome (Aran 2016 PMID: 27164683, Guemez-Gamboa 2018 PMID: 30178464, Fazeli 2021 PMID: 34773825). Additionally, ex vivo functional studies using a cortical organoid model from human stem cell line knockouts that were missing the PCDH12 protein have shown that loss of PCDH12 severely impairs cerebral organoid development with reduced proliferative areas and disrupted laminar organization (Rakotomamonjy 2023 PMID: 37480564), which is in line with the clinical phenotype observed in patients. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive diencephalic mesencephalic junction dysplasia syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.

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
PCDH12 loss results in premature neuronal differentiation and impeded migration in a cortical organoid model.	Rakotomamonjy J	Cell reports	2023	PMID: 37480564
The phenotypic spectrum of PCDH12 associated disorders - Five new cases and review of the literature.	Fazeli W	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2022	PMID: 34773825
Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.	Guemez-Gamboa A	Annals of neurology	2018	PMID: 30178464
Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection.	Aran A	Neurology	2016	PMID: 27164683

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_016580.4(PCDH12):c.954C>A (p.Tyr318Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...