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NM_000303.3(PMM2):c.618C>A (p.Phe206Leu) AND PMM2-congenital disorder of glycosylation

Germline classification:
Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:
Jul 10, 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:
RCV000672270.6

Allele description [Variation Report for NM_000303.3(PMM2):c.618C>A (p.Phe206Leu)]

NM_000303.3(PMM2):c.618C>A (p.Phe206Leu)

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.618C>A (p.Phe206Leu)
HGVS:
  • NC_000016.10:g.8813085C>A
  • NG_009209.1:g.20273C>A
  • NM_000303.3:c.618C>AMANE SELECT
  • NP_000294.1:p.Phe206Leu
  • NC_000016.9:g.8906942C>A
  • NM_000303.2:c.618C>A
Protein change:
F206L
Links:
dbSNP: rs1460691341
NCBI 1000 Genomes Browser:
rs1460691341
Molecular consequence:
  • NM_000303.3:c.618C>A - 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
SCV000797361Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Uncertain significance
(Jan 23, 2018)
unknownclinical testing

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

Citation Link,

SCV003443485Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jul 10, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Congenital disorder of glycosylation type Ia in a Malaysian family: clinical outcome and description of a novel PMM2 mutation.

Thong MK, Fietz M, Nicholls C, Lee MH, Asma O.

J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S41-4. doi: 10.1007/s10545-009-1031-1. Epub 2009 Jan 26.

PubMed [citation]
PMID:
19165618

DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG).

Schollen E, Martens K, Geuzens E, Matthijs G.

Eur J Hum Genet. 2002 Oct;10(10):643-8.

PubMed [citation]
PMID:
12357336
See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000797361.1

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443485.2

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 206 of the PMM2 protein (p.Phe206Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 19165618). 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: 556280). 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. This variant disrupts the p.Phe206 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 12357336), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jan 19, 2025