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NM_000303.3(PMM2):c.728T>C (p.Leu243Pro) AND PMM2-congenital disorder of glycosylation

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Sep 8, 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:
RCV002261482.5

Allele description [Variation Report for NM_000303.3(PMM2):c.728T>C (p.Leu243Pro)]

NM_000303.3(PMM2):c.728T>C (p.Leu243Pro)

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.728T>C (p.Leu243Pro)
HGVS:
  • NC_000016.10:g.8847812T>C
  • NG_009209.1:g.55000T>C
  • NM_000303.3:c.728T>CMANE SELECT
  • NP_000294.1:p.Leu243Pro
  • NC_000016.9:g.8941669T>C
  • NM_000303.2:c.728T>C
Protein change:
L243P
Links:
dbSNP: rs2060937980
NCBI 1000 Genomes Browser:
rs2060937980
Molecular consequence:
  • NM_000303.3:c.728T>C - 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
SCV002540746Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jul 5, 2022)
inheritedclinical testing

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

SCV003443487Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

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

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
whiteinheritedyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides.

Haeuptle MA, Hennet T.

Hum Mutat. 2009 Dec;30(12):1628-41. doi: 10.1002/humu.21126. Review.

PubMed [citation]
PMID:
19862844

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
See all PubMed Citations (3)

Details of each submission

From Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic, SCV002540746.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1white1not providednot providedclinical testing PubMed (2)

Description

The variant c.728T>C (p.Leu243Pro) is a missense substitution in exon 8 of8 that results in the alteration of the codon at amino acid position 243. The variant has not been listed in gnomAD or dbSNP. This variant has been previously reported as a disease-causing mutation by the Human Gene Mutation Database (HGMD, CM055486) with association with PMM2-CDG. In addition, the variant has been reported by Haeuptle et al, 2009 in a patient with CDG.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443487.2

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

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1693586). This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 243 of the PMM2 protein (p.Leu243Pro).

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

Last Updated: Jan 13, 2025