NM_000303.3(PMM2):c.722G>C (p.Cys241Ser) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Aug 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000153745.26

Allele description [Variation Report for NM_000303.3(PMM2):c.722G>C (p.Cys241Ser)]

NM_000303.3(PMM2):c.722G>C (p.Cys241Ser)

Gene:

PMM2:phosphomannomutase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.2

Genomic location:

Preferred name:

NM_000303.3(PMM2):c.722G>C (p.Cys241Ser)

HGVS:

NC_000016.10:g.8847806G>C
NG_009209.1:g.54994G>C
NM_000303.3:c.722G>CMANE SELECT
NP_000294.1:p.Cys241Ser
NP_000294.1:p.Cys241Ser
NC_000016.9:g.8941663G>C
NM_000303.2:c.722G>C
O15305:p.Cys241Ser

Protein change:

C241S; CYS241SER

Links:

UniProtKB: O15305#VAR_022510; OMIM: 601785.0012; dbSNP: rs80338709

NCBI 1000 Genomes Browser:

rs80338709

Molecular consequence:

NM_000303.3:c.722G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000232518	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Jan 3, 2014)	germline	clinical testing	Citation Link,
SCV000610219	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001905596	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001959832	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001968201	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002067359	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002072677	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 8, 2024)	germline	clinical testing	Citation Link,
SCV004224101	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10527672, 11715002, 21541725, 26014514, 28425223, 28566178, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phosphomannomutase deficiency: the molecular basis of the classical Jaeken syndrome (CDGS type Ia).

Matthijs G, Schollen E, Heykants L, Grünewald S.

Mol Genet Metab. 1999 Oct;68(2):220-6. Review. No abstract available.

PubMed [citation]

PMID:: 10527672

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia.

Westphal V, Peterson S, Patterson M, Tournay A, Blumenthal A, Treacy EP, Freeze HH.

Genet Med. 2001 Nov-Dec;3(6):393-8.

PubMed [citation]

PMID:: 11715002

See all PubMed Citations (7)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000232518.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000610219.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.000139	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001905596.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968201.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002067359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.722G>C, in exon 8 that results in an amino acid change, p.Cys241Ser. This sequence change has been described in the gnomAD database with a frequency of 0.06% in the African population (dbSNP rs80338709). The p.Cys241Ser change has been described in the compound heterozygous state with a second pathogenic mutation in multiple individuals with a mild form of congenital disorder of glycosylation type Ia (CDG Ia) (PMIDs 11715002, 21541725, 28425223, 28566178, 22012410, 10527672). Functional analyses have demonstrated that the p.Cys241Ser change affects folding of the PMM2 protein, leading to abnormal protein aggregation and intermediate residual PMM2 activity (PMIDs 26014514, 21541725). The p.Cys241Ser change affects a moderately conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Cys241Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002072677.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate C241S reduced enzyme activity and affected folding properties of the PMM2 protein (PMID: 26014514); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 33643843, 30293989, 22012410, 21541725, 28425223, 11715002, 28566178, 29482223, 30304743, 31307013, 32630370, 31115488, 33163565, 33413482, 35279850, 35531120, 32860008, 34480478, 33879512, 34828263, 26014514, 10527672)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004224101.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

PP1, PP3, PP4, PM2, PM3_strong, PS4_moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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