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NM_000303.3(PMM2):c.349G>T (p.Gly117Cys) AND PMM2-congenital disorder of glycosylation

Germline classification:
Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:
Aug 20, 2021
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:
RCV001089469.6

Allele description [Variation Report for NM_000303.3(PMM2):c.349G>T (p.Gly117Cys)]

NM_000303.3(PMM2):c.349G>T (p.Gly117Cys)

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.349G>T (p.Gly117Cys)
HGVS:
  • NC_000016.10:g.8811080G>T
  • NG_009209.1:g.18268G>T
  • NM_000303.3:c.349G>TMANE SELECT
  • NP_000294.1:p.Gly117Cys
  • NC_000016.9:g.8904937G>T
  • NC_000016.9:g.8904937G>T
  • NM_000303.2:c.349G>T
  • p.(Gly117Cys)
Protein change:
G117C
Links:
dbSNP: rs104894530
NCBI 1000 Genomes Browser:
rs104894530
Molecular consequence:
  • NM_000303.3:c.349G>T - missense variant - [Sequence Ontology: SO:0001583]
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
SCV000998573Pediatric Metabolic Diseases, Hacettepe University
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenicgermlineclinical testing

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

SCV001451942Pediatrics, MediClubGeorgia
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 1, 2020)
unknownclinical testing

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

SCV002949674Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Aug 20, 2021)
germlineclinical testing

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

Summary from all submissions

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Pediatric Metabolic Diseases, Hacettepe University, SCV000998573.1

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

From Pediatrics, MediClubGeorgia, SCV001451942.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (1)

Description

The PMM2 variant c.349G>T p.(Gly117Cys) causes an amino acid change from Gly to Cys at position 117. The substitution is in close proximity to the highly conserved acceptor splice site. This variant is absent in population databases and in clinvar is submitted as a likely pathogenic. Algorithms developed to predict the effect of missense variants showed:PolyPhen: Probablydamaging; Align-GVGD: C0; SIFT: Deleterious; MutationTaster: Disease-causing; Conservation_nt: high; Conservation_aa: high 2/2 likely splice effect;

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002949674.1

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

Description

This sequence change replaces glycine with cysteine at codon 117 of the PMM2 protein (p.Gly117Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PMM2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Jan 19, 2025