NM_002435.3(MPI):c.1253G>A (p.Arg418His) AND MPI-congenital disorder of glycosylation

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 14, 2024
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:: RCV000202324.4

Allele description [Variation Report for NM_002435.3(MPI):c.1253G>A (p.Arg418His)]

NM_002435.3(MPI):c.1253G>A (p.Arg418His)

Gene:

MPI:mannose phosphate isomerase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q24.1

Genomic location:

Preferred name:

NM_002435.3(MPI):c.1253G>A (p.Arg418His)

HGVS:

NC_000015.10:g.74897711G>A
NG_008921.1:g.12643G>A
NM_001289155.2:c.*180G>A
NM_001289156.2:c.1103G>A
NM_001289157.2:c.1070G>A
NM_001330372.2:c.1193G>A
NM_002435.3:c.1253G>AMANE SELECT
NP_001276085.1:p.Arg368His
NP_001276086.1:p.Arg357His
NP_001317301.1:p.Arg398His
NP_002426.1:p.Arg418His
NC_000015.9:g.75190052G>A
NM_002435.2:c.1253G>A
P34949:p.Arg418His

Protein change:

R357H

Links:

UniProtKB: P34949#VAR_022524; dbSNP: rs863225087

NCBI 1000 Genomes Browser:

rs863225087

Molecular consequence:

NM_001289155.2:c.*180G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001289156.2:c.1103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289157.2:c.1070G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330372.2:c.1193G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002435.3:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: MPI-congenital disorder of glycosylation
Synonyms:: CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ib; CDG Ib; MANNOSEPHOSPHATE ISOMERASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011257; MedGen: C1865145; Orphanet: 79319; OMIM: 602579

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000256095	Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute See additional submitters Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	research	PubMed (1) [See all records that cite this PMID]
SCV004195524	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 14, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000256095

Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

inherited

research

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

SCV004195524

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 14, 2024)

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	research

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

Details of each submission

From Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, SCV000256095.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

This variant was identified in a male who presented clinically normal until the age of 2 when he became ill with persistent vomiting and venous sinus thrombosis which resulted in a massive stroke. Subsequently he developed a seizure disorder and delayed development. Full metabolic work up was normal except for the presence of a Type I CDG profile. Given his history of normal development prior to the stroke, MPI-CDG was suggested. Enzyme assay concluded he had MPI-CDG. The enzyme assay was performed as previously reported from the Freeze lab, PMID: 9525984. “Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy.” Genetic analysis revealed two single nucleotide variants inherited in a compound heterozygous fashion, NM_002435.2:c.1205A>G and NM_002435.2:c.1253G>A. The c.1253G>A variant has not been previously reported in ExAc, dbSNP or ESP, however it has been reported in COSMIC (Catalogue of Somatic Mutations in Cancer). In COSMIC, the mutation was seen in breast tissue with a sample size of 15 but the mutation was not confirmed to be somatic. The predicted protein change for NM_002435.2 is an Arginine to Histidine, which has been previously reported in SwissProt as a disease associated variant leading to CDG-Ib. This residue is highly conserved (humans through s. cerevisae with the exception of D. melanogaster).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004195524.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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