VCV001704910.8 - ClinVar

NM_003620.4(PPM1D):c.1280G>A (p.Trp427Ter)

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.

(6)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003620.4(PPM1D):c.1280G>A (p.Trp427Ter)

Variation ID: 1704910 Accession: VCV001704910.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q23.2 17: 60663014 (GRCh38) [ NCBI UCSC ] 17: 58740375 (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	Sep 17, 2022	Aug 4, 2024	Apr 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003620.4:c.1280G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003611.1:p.Trp427Ter	nonsense
NC_000017.11:g.60663014G>A
NC_000017.10:g.58740375G>A
NG_023265.1:g.67822G>A
LRG_770:g.67822G>A
LRG_770t1:c.1280G>A	LRG_770p1:p.Trp427Ter

... more HGVS ... less HGVS

Protein change

W427*

Other names

Canonical SPDI

NC_000017.11:60663013:G:A

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.
PPM1D		No evidence available	No evidence available	GRCh38 GRCh37	275	309

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.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 10, 2022	RCV002283237.5
Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 4, 2024	RCV002464553.4

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.
Pathogenic (Sep 10, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002571486.2 First in ClinVar: Sep 17, 2022 Last updated: Mar 04, 2023	Comment: Has not been previously reported as a pathogenic or benign germline variant to our knowledge; Has been reported as a somatic mosaic variant in ovarian … (more) Has not been previously reported as a pathogenic or benign germline variant to our knowledge; Has been reported as a somatic mosaic variant in ovarian cancer tumors. These variants were thought to be treatment related and not associated with a predisposition to cancer (Pharoah et al., 2016; Weber-Lassalle et al., 2018); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27401275, 30216591, 26823519) (less)
Pathogenic (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, University of Torino Study: NeuroWES Accession: SCV002760134.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022
Pathogenic (May 03, 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: SCV003503314.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28343630 Comment: This sequence change creates a premature translational stop signal (p.Trp427) in the PPM1D gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Trp427) in the PPM1D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the PPM1D protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Jansen de Vries syndrome (PMID: 28343630). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004810165.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Pathogenic (Mar 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005091082.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024	Comment: PVS1, PM2, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 1704910). This variant has been previously reported … (more) PVS1, PM2, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 1704910). This variant has been previously reported as causative (PMID:28343630). (less)
Pathogenic (Mar 10, 2021)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031377.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)

Comment:

Has not been previously reported as a pathogenic or benign germline variant to our knowledge; Has been reported as a somatic mosaic variant in ovarian cancer tumors. These variants were thought to be treatment related and not associated with a predisposition to cancer (Pharoah et al., 2016; Weber-Lassalle et al., 2018); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27401275, 30216591, 26823519)

Comment:

This sequence change creates a premature translational stop signal (p.Trp427*) in the PPM1D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the PPM1D protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Jansen de Vries syndrome (PMID: 28343630). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic.

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
De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.	Jansen S	American journal of human genetics	2017	PMID: 28343630

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_003620.4(PPM1D):c.1280G>A (p.Trp427Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...