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NM_000303.3(PMM2):c.203T>G (p.Phe68Cys) AND PMM2-congenital disorder of glycosylation

Germline classification:
Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:
Sep 8, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV001849246.8

Allele description [Variation Report for NM_000303.3(PMM2):c.203T>G (p.Phe68Cys)]

NM_000303.3(PMM2):c.203T>G (p.Phe68Cys)

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.203T>G (p.Phe68Cys)
HGVS:
  • NC_000016.10:g.8804791T>G
  • NG_009209.1:g.11979T>G
  • NM_000303.3:c.203T>GMANE SELECT
  • NP_000294.1:p.Phe68Cys
  • NC_000016.9:g.8898648T>G
  • NM_000303.2:c.203T>G
Protein change:
F68C
Links:
dbSNP: rs373788015
NCBI 1000 Genomes Browser:
rs373788015
Molecular consequence:
  • NM_000303.3:c.203T>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
unknown functional consequence
Observations:
1

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
SCV002106380Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Feb 17, 2020)
unknownclinical testing

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

SCV002265068Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 8, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications.

Ligezka AN, Radenkovic S, Saraswat M, Garapati K, Ranatunga W, Krzysciak W, Yanaihara H, Preston G, Brucker W, McGovern RM, Reid JM, Cassiman D, Muthusamy K, Johnsen C, Mercimek-Andrews S, Larson A, Lam C, Edmondson AC, Ghesquière B, Witters P, Raymond K, Oglesbee D, et al.

Ann Neurol. 2021 Dec;90(6):887-900. doi: 10.1002/ana.26245. Epub 2021 Oct 26.

PubMed [citation]
PMID:
34652821
PMCID:
PMC8820356
See all PubMed Citations (3)

Details of each submission

From Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic, SCV002106380.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (2)

Description

Elevated liver transaminases, coagulation abnormalities, developmental delay, speech delay, ataxia, muscle weakness, strabismus, abnormal movements, esotropia, transferrin testing consistent with CDG type I and PMM2-CDG.

Description

This sequence change replaces phenylalanine with cysteine at codon 68 of the PMM2 protein (p.Phe68Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine (PP3). In addition, this variant is absent in the normal population (C=0.00000 (0/14050, ALFA)) (PM2). SIFT, PolyPhen2 and Align-GCGD all suggest that the variant is likely damaging (PP3). Patient has another pathogenic variant in the same gene (PMM2 p.Arg141His). Missense variants in nearby residues reported as pathogenic in individuals with PMM2-CDG (PP2). Patient's phenotype is consistent with PMM2-CDG diagnosis (PP4). Though there is a lot of supporting evidence, at this time there is insufficient evidence to clearly evaluate this variant. Therefore, we classify it as a VUS.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002265068.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital disorders of glycosylation (PMID: 34652821; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1344574). 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. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 68 of the PMM2 protein (p.Phe68Cys).

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

Last Updated: Jan 19, 2025