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NM_000303.3(PMM2):c.458T>G (p.Ile153Arg) AND PMM2-congenital disorder of glycosylation

Germline classification:
Conflicting classifications of pathogenicity (3 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:
RCV001945657.10

Allele description [Variation Report for NM_000303.3(PMM2):c.458T>G (p.Ile153Arg)]

NM_000303.3(PMM2):c.458T>G (p.Ile153Arg)

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.458T>G (p.Ile153Arg)
HGVS:
  • NC_000016.10:g.8811648T>G
  • NG_009209.1:g.18836T>G
  • NM_000303.3:c.458T>GMANE SELECT
  • NP_000294.1:p.Ile153Arg
  • NC_000016.9:g.8905505T>G
  • NM_000303.2:c.458T>G
Protein change:
I153R
Links:
dbSNP: rs150577656
NCBI 1000 Genomes Browser:
rs150577656
Molecular consequence:
  • NM_000303.3:c.458T>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
SCV002191714Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

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

PubMed (5)
[See all records that cite these PMIDs]

SCV002768343Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Oct 19, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003920331Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jul 15, 2022)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002191714.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

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). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 153 of the PMM2 protein (p.Ile153Arg). This variant is present in population databases (no rsID available, 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: 1422606). 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. 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 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.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768343.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PMM2-congenital disorder of glycosylation (PMM2-CDG). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to arginine (exon 6). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PMM domain (NCBI, Decipher, PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a threonine has been shown to cause PMM2-CDG (ClinVar, PMID: 26502900, 30991241). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant, p.(Val231Met) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001740). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920331.1

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

Description

This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:1422606). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this position have been reported in association with disease (p.Ile153Met, p.Ile153Thr) supporting the potential functional relevance of this codon. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, the clinical significance of this variant is uncertain.

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

Last Updated: Jan 19, 2025