VCV000188744.41 - ClinVar

NM_000303.3(PMM2):c.24del (p.Cys9fs)

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.

(10)

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_000303.3(PMM2):c.24del (p.Cys9fs)

Variation ID: 188744 Accession: VCV000188744.41

Type and length

Deletion, 1 bp

Location

Cytogenetic: 16p13.2 16: 8797906 (GRCh38) [ NCBI UCSC ] 16: 8891763 (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	Mar 29, 2015	Oct 20, 2024	Feb 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000303.3:c.24del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000294.1:p.Cys9fs	frameshift
NM_000303.3:c.24delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000303.2:c.24del
NC_000016.10:g.8797906del
NC_000016.9:g.8891763del
NG_009209.1:g.5094del
NG_033146.1:g.4743del

... more HGVS ... less HGVS

Protein change

C9fs

Other names

Canonical SPDI

NC_000016.10:8797905:C:

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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA273902 dbSNP: rs768021123 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.
PMM2		-	-	GRCh38 GRCh37	776	875

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.
PMM2-congenital disorder of glycosylation	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Feb 21, 2024	RCV000169057.16
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 11, 2023	RCV001091537.24
PMM2-related disorder	Pathogenic (1)	criteria provided, single submitter	Oct 27, 2022	RCV003422060.4

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 (Jul 27, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Carbohydrate-deficient glycoprotein syndrome type I Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000920017.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (4) PubMed: 18093857‚ 12529711‚ 15844218‚ 11715002 Comment: Variant summary: PMM2 c.24delC (p.Cys9AlafsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: PMM2 c.24delC (p.Cys9AlafsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.7e-05 in 236838 control chromosomes. c.24delC has been reported in the literature in individuals affected with Congenital Disorder of Glycosylation Type 1a (Arnoux_2008, Le Bizec_2005, Schollen_2002, Westphal_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which showed the variant to have <10% enzyme activity in a yeast expression system (Westphal_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (Apr 04, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Carbohydrate-deficient glycoprotein syndrome type I (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220219.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 12297897‚ 18093857‚ 11058895‚ 19168813
Pathogenic (Jan 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PMM2-congenital disorder of glycosylation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002795486.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 11, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004030644.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Comment: Published functional studies demonstrate a damaging effect of reduction of PMM activity to negative control level (PMID: 11715002); Frameshift variant predicted to result in protein … (more) Published functional studies demonstrate a damaging effect of reduction of PMM activity to negative control level (PMID: 11715002); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12297897, 12529711, 11058895, 18093857, 33643843, 19168813, 11715002, 15844218) (less)
Pathogenic (Oct 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PMM2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004117937.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The PMM2 c.24delC variant is predicted to result in a frameshift and premature protein termination (p.Cys9Alafs27). This variant has been reported in individuals with autosomal … (more) The PMM2 c.24delC variant is predicted to result in a frameshift and premature protein termination (p.Cys9Alafs27). This variant has been reported in individuals with autosomal recessive congenital disorder of glycosylation 1a (Matthijs et al. 2000. PubMed ID: 11058895; Jamroz et al. 2009. PubMed ID: 19168813; Westphal et al. 2001. PubMed ID: 11715002). This variant is reported in 0.0037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-8891762-TC-T). Frameshift variants in PMM2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	PMM2-congenital disorder of glycosylation Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000832586.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 28492532‚ 19862844‚ 11058895‚ 12297897‚ 18093857‚ 19168813 Comment: This sequence change creates a premature translational stop signal (p.Cys9Alafs27) in the PMM2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Cys9Alafs27) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs768021123, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with congenital disorder of glycosylation (PMID: 11058895, 12297897, 18093857, 19168813). ClinVar contains an entry for this variant (Variation ID: 188744). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 21, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PMM2-congenital disorder of glycosylation Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205260.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jun 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247653.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PMM2: PM3:Strong, PVS1:Strong, PM2 Number of individuals with the variant: 3
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009269.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Congenital disorder of glycosylation type 1a Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457162.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

Variant summary: PMM2 c.24delC (p.Cys9AlafsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.7e-05 in 236838 control chromosomes. c.24delC has been reported in the literature in individuals affected with Congenital Disorder of Glycosylation Type 1a (Arnoux_2008, Le Bizec_2005, Schollen_2002, Westphal_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which showed the variant to have <10% enzyme activity in a yeast expression system (Westphal_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Published functional studies demonstrate a damaging effect of reduction of PMM activity to negative control level (PMID: 11715002); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12297897, 12529711, 11058895, 18093857, 33643843, 19168813, 11715002, 15844218)

Comment:

The PMM2 c.24delC variant is predicted to result in a frameshift and premature protein termination (p.Cys9Alafs*27). This variant has been reported in individuals with autosomal recessive congenital disorder of glycosylation 1a (Matthijs et al. 2000. PubMed ID: 11058895; Jamroz et al. 2009. PubMed ID: 19168813; Westphal et al. 2001. PubMed ID: 11715002). This variant is reported in 0.0037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-8891762-TC-T). Frameshift variants in PMM2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Cys9Alafs*27) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs768021123, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with congenital disorder of glycosylation (PMID: 11058895, 12297897, 18093857, 19168813). ClinVar contains an entry for this variant (Variation ID: 188744). 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
Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides.	Haeuptle MA	Human mutation	2009	PMID: 19862844
CDG type Ia and congenital cytomegalovirus infection: two coexisting conditions.	Jamroz E	Journal of child neurology	2009	PMID: 19168813
Risk assessment of acute vascular events in congenital disorder of glycosylation type Ia.	Arnoux JB	Molecular genetics and metabolism	2008	PMID: 18093857
A new insight into PMM2 mutations in the French population.	Le Bizec C	Human mutation	2005	PMID: 15844218
PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning.	Schollen E	European journal of human genetics : EJHG	2003	PMID: 12529711
Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia.	Marquardt T	European journal of pediatrics	2002	PMID: 12297897
Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia.	Westphal V	Genetics in medicine : official journal of the American College of Medical Genetics	2001	PMID: 11715002
Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia).	Matthijs G	Human mutation	2000	PMID: 11058895

Text-mined citations for rs768021123 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000303.3(PMM2):c.24del (p.Cys9fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs768021123 ...