NM_000303.3(PMM2):c.677C>G (p.Thr226Ser) AND PMM2-CDG

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Apr 1, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000008161.6

Allele description

NM_000303.3(PMM2):c.677C>G (p.Thr226Ser)

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.677C>G (p.Thr226Ser)

HGVS:

NC_000016.10:g.8847761C>G
NG_009209.1:g.54949C>G
NM_000303.3:c.677C>GMANE SELECT
NP_000294.1:p.Thr226Ser
NC_000016.9:g.8941618C>G
NM_000303.2:c.677C>G
O15305:p.Thr226Ser

Protein change:

T226S; THR226SER

Links:

UniProtKB: O15305#VAR_022505; OMIM: 601785.0017; dbSNP: rs80338706

NCBI 1000 Genomes Browser:

rs80338706

Molecular consequence:

NM_000303.3:c.677C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PMM2-CDG
Synonyms:: CDG Ia; CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE Ia; CDG 1A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008907; MedGen: C0349653; Orphanet: 79318; OMIM: 212065

Recent activity

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choline transporter-like protein 2 isoform X4 [Phascolarctos cinereus]
choline transporter-like protein 2 isoform X4 [Phascolarctos cinereus]
gi|1190400982|ref|XP_020850609.1|

Protein
PREDICTED: Pan troglodytes fibroblast growth factor 11 (FGF11), transcript varia...
PREDICTED: Pan troglodytes fibroblast growth factor 11 (FGF11), transcript variant X1, mRNA
gi|2697747998|ref|XM_009431743.4|

Nucleotide
PREDICTED: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 isoform X2 [Ch...
PREDICTED: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 isoform X2 [Chinchilla lanigera]
gi|918629052|ref|XP_013358310.1|

Protein
Mus musculus amidohydrolase domain containing 2 (Amdhd2), mRNA
Mus musculus amidohydrolase domain containing 2 (Amdhd2), mRNA
gi|146198690|ref|NM_172935.4|

Nucleotide
kirrel3l [Cheilinus undulatus]
kirrel3l [Cheilinus undulatus]
Gene ID:121513360

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000028366	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2000)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000040588	GeneReviews	no assertion criteria provided	pathologic (Apr 21, 2011)	not provided	curation
SCV002511473	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 1, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10922383, 11134235, 12705494, 33340551 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000028366

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2000)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000040588

GeneReviews

no assertion criteria provided

pathologic
(Apr 21, 2011)

not provided

curation

SCV002511473

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 1, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Identification of four novel PMM2 mutations in congenital disorders of glycosylation (CDG) Ia French patients.

Vuillaumier-Barrot S, Hetet G, Barnier A, Dupré T, Cuer M, de Lonlay P, Cormier-Daire V, Durand G, Grandchamp B, Seta N.

J Med Genet. 2000 Aug;37(8):579-80.

PubMed [citation]

PMID:: 10922383
PMCID:: PMC1734666

A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases.

de Lonlay P, Seta N, Barrot S, Chabrol B, Drouin V, Gabriel BM, Journel H, Kretz M, Laurent J, Le Merrer M, Leroy A, Pedespan D, Sarda P, Villeneuve N, Schmitz J, van Schaftingen E, Matthijs G, Jaeken J, Korner C, Munnich A, Saudubray JM, Cormier-Daire V.

J Med Genet. 2001 Jan;38(1):14-9.

PubMed [citation]

PMID:: 11134235
PMCID:: PMC1734729

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000028366.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a French patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified compound heterozygosity for 2 mutations in the PMM2 gene: a 677C-G transversion in exon 8 resulting in a thr226-to-ser (T226S) substitution, and R141H (601785.0001).

#	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	not provided	not provided	not provided

From GeneReviews, SCV000040588.1

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

Description

Converted during submission to Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511473.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: PMM2 c.677C>G (p.Thr226Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251300 control chromosomes. c.677C>G has been reported in the literature as compound heterozygous genotypes in individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Vuillaumier-Barrot_2000, de Lonlay_2001, Briones_2002, Quelhas_2021). 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 example, Vuillaumier-Barrot_2000). The most pronounced variant effect results in 10%-<30% of normal Phosphomannomutase enzyme activity in-vitro. 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 likely pathogenic.

#	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		not provided	not provided	not provided	not provided

Last Updated: May 24, 2022

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