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NM_000303.3(PMM2):c.713G>C (p.Arg238Pro) AND PMM2-congenital disorder of glycosylation

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
May 13, 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:
RCV001808280.6

Allele description [Variation Report for NM_000303.3(PMM2):c.713G>C (p.Arg238Pro)]

NM_000303.3(PMM2):c.713G>C (p.Arg238Pro)

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.713G>C (p.Arg238Pro)
HGVS:
  • NC_000016.10:g.8847797G>C
  • NG_009209.1:g.54985G>C
  • NM_000303.3:c.713G>CMANE SELECT
  • NP_000294.1:p.Arg238Pro
  • NC_000016.9:g.8941654G>C
  • NM_000303.2:c.713G>C
Protein change:
R238P
Links:
dbSNP: rs151319324
NCBI 1000 Genomes Browser:
rs151319324
Molecular consequence:
  • NM_000303.3:c.713G>C - 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
SCV0020589423billion
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jan 3, 2022)
germlineclinical testing

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

PMID:11058895,

SCV002238805Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Mar 16, 2022)
germlineclinical testing

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

SCV004205284Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 13, 2023)
unknownclinical 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
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate-deficient glycoprotein syndrome type 1.

Kondo I, Mizugishi K, Yoneda Y, Hashimoto T, Kuwajima K, Yuasa I, Shigemoto K, Kuroda Y.

Clin Genet. 1999 Jan;55(1):50-4.

PubMed [citation]
PMID:
10066032

Application of whole exome sequencing to a rare inherited metabolic disease with neurological and gastrointestinal manifestations: a congenital disorder of glycosylation mimicking glycogen storage disease.

Choi R, Woo HI, Choe BH, Park S, Yoon Y, Ki CS, Lee SY, Kim JW, Song J, Kim DS, Kwon S, Park HD.

Clin Chim Acta. 2015 Apr 15;444:50-3. doi: 10.1016/j.cca.2015.02.008. Epub 2015 Feb 11.

PubMed [citation]
PMID:
25681648
See all PubMed Citations (4)

Details of each submission

From 3billion, SCV002058942.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMM2 related disorder (PMID:9497260, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25681648, PM3_M). A different missense change at the same codon has been reported to be associated with PMM2 related disorder (PMID:11058895, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.723, PP3_P). A missense variant is a common mechanism associated with Congenital disorder of glycosylation (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002238805.3

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

Description

ClinVar contains an entry for this variant (Variation ID: 1333592). 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. This missense change has been observed in individual(s) with congenital disorder of glycosylation Ia (PMID: 10066032, 25681648). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs151319324, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 238 of the PMM2 protein (p.Arg238Pro).

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

From Baylor Genetics, SCV004205284.1

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

Last Updated: Jan 13, 2025