NM_000303.3(PMM2):c.459A>G (p.Ile153Met) AND PMM2-congenital disorder of glycosylation

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 18, 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:: RCV003619917.1

Allele description [Variation Report for NM_000303.3(PMM2):c.459A>G (p.Ile153Met)]

NM_000303.3(PMM2):c.459A>G (p.Ile153Met)

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.459A>G (p.Ile153Met)

HGVS:

NC_000016.10:g.8811649A>G
NG_009209.1:g.18837A>G
NM_000303.3:c.459A>GMANE SELECT
NP_000294.1:p.Ile153Met
NC_000016.9:g.8905506A>G

Protein change:

I153M

Molecular consequence:

NM_000303.3:c.459A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PMM2-congenital disorder of glycosylation
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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004375337	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 18, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11058895, 11156536, 25497157, 26502900, 33163565, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004375337

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 18, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Citations

PubMed

Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia).

Matthijs G, Schollen E, Bjursell C, Erlandson A, Freeze H, Imtiaz F, Kjaergaard S, Martinsson T, Schwartz M, Seta N, Vuillaumier-Barrot S, Westphal V, Winchester B.

Hum Mutat. 2000 Nov;16(5):386-94.

PubMed [citation]

PMID:: 11058895

High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency).

Grünewald S, Schollen E, Van Schaftingen E, Jaeken J, Matthijs G.

Am J Hum Genet. 2001 Feb;68(2):347-54. Epub 2001 Jan 11.

PubMed [citation]

PMID:: 11156536
PMCID:: PMC1235268

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV004375337.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ile153 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11058895, 11156536, 25497157, 26502900; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function. This missense change has been observed in individual(s) with clinical features of PMM2-congenital disorder of glycosylation (PMID: 33163565). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 153 of the PMM2 protein (p.Ile153Met).

#	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: Feb 28, 2024

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