NM_000303.3(PMM2):c.337C>A (p.Pro113Thr) AND PMM2-congenital disorder of glycosylation

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 14, 2023
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:: RCV000984293.3

Allele description [Variation Report for NM_000303.3(PMM2):c.337C>A (p.Pro113Thr)]

NM_000303.3(PMM2):c.337C>A (p.Pro113Thr)

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.337C>A (p.Pro113Thr)

HGVS:

NC_000016.10:g.8806397C>A
NG_009209.1:g.13585C>A
NM_000303.3:c.337C>AMANE SELECT
NP_000294.1:p.Pro113Thr
NC_000016.9:g.8900254C>A
NM_000303.2:c.337C>A

Protein change:

P113T

Links:

dbSNP: rs765433263

NCBI 1000 Genomes Browser:

rs765433263

Molecular consequence:

NM_000303.3:c.337C>A - 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
SCV001132462	Counsyl	no assertion criteria provided	Uncertain significance (Jan 24, 2019)	unknown	clinical testing
SCV003491859	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9140401, 11058895, 18948042, 21541725, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001132462

Counsyl

no assertion criteria provided

Uncertain significance
(Jan 24, 2019)

unknown

clinical testing

SCV003491859

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 14, 2023)

germline

clinical testing

PubMed (5)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome).

Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, Van Schaftingen E.

Nat Genet. 1997 May;16(1):88-92. Erratum in: Nat Genet 1997 Jul;16(3):316.

PubMed [citation]

PMID:: 9140401

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

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV001132462.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003491859.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 113 of the PMM2 protein (p.Pro113Thr). This variant is present in population databases (rs765433263, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PMM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420784). 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 variant disrupts the p.Pro113 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9140401, 11058895, 18948042, 21541725). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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: Sep 1, 2024

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