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NM_000303.3(PMM2):c.677C>G (p.Thr226Ser) AND PMM2-congenital disorder of glycosylation

Germline classification:
Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:
Nov 22, 2023
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:
RCV000008161.12

Allele description [Variation Report for NM_000303.3(PMM2):c.677C>G (p.Thr226Ser)]

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-congenital disorder of glycosylation
Synonyms:
CDG Ia; JAEKEN SYNDROME; PHOSPHOMANNOMUTASE 2 DEFICIENCY; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008907; MedGen: C0349653; Orphanet: 79318; OMIM: 212065

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000028366OMIM
no assertion criteria provided
Pathogenic
(Aug 1, 2000)
germlineliterature only

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

SCV000040588GeneReviews
no classification provided
not providedunknownliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV002511473Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Apr 1, 2022)
germlineclinical testing

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

Citation Link,

SCV003441820Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 3, 2021)
germlineclinical testing

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

SCV004205309Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 22, 2023)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownnot providednot providednot providednot providednot providednot providedliterature only
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

PMM2-CDG..

Lam C, Krasnewich DM.

2005 Aug 15 [updated 2021 May 20]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

PubMed [citation]
PMID:
20301289

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 (9)

Details of each submission

From OMIM, SCV000028366.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000040588.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441820.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Experimental studies have shown that this missense change affects PMM2 function (PMID: 10922383). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 7722). This missense change has been observed in individual(s) with PMM2-related conditions (PMID: 10922383, 11156536, 17166182). This variant is present in population databases (rs80338706, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 226 of the PMM2 protein (p.Thr226Ser). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004205309.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 13, 2025