VCV000218095.3 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

2 out of 2 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 218095 Accession: VCV000218095.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q24.1 15: 74897711 (GRCh38) [ NCBI UCSC ] 15: 75190052 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 25, 2015	Jun 17, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002435.3:c.1253G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002426.1:p.Arg418His	missense
NM_001289155.2:c.*180G>A		3 prime UTR
NM_001289156.2:c.1103G>A	NP_001276085.1:p.Arg368His	missense
NM_001289157.2:c.1070G>A	NP_001276086.1:p.Arg357His	missense
NM_001330372.2:c.1193G>A	NP_001317301.1:p.Arg398His	missense
NC_000015.10:g.74897711G>A
NC_000015.9:g.75190052G>A
NG_008921.1:g.12643G>A
	P34949:p.Arg418His

... more HGVS ... less HGVS

Protein change

R418H, R357H, R368H, R398H

Other names

Canonical SPDI

NC_000015.10:74897710:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA279842 UniProtKB: P34949#VAR_022524 dbSNP: rs863225087 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MPI		-	-	GRCh38 GRCh37	590	644

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
MPI-congenital disorder of glycosylation	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000202324.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MPI-congenital disorder of glycosylation	Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute Additional submitter: Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health Accession: SCV000256095.1 First in ClinVar: Nov 25, 2015 Last updated: Nov 25, 2015	Comment: show 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). (less) Observation: 1 Collection method: research Allele origin: inherited Affected status: yes Observation 1 Collection method: research Allele origin: inherited Affected status: yes

Likely pathogenic (Mar 14, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MPI-congenital disorder of glycosylation	Baylor Genetics Accession: SCV004195524.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

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).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation.	Kane MS	American journal of human genetics	2016	PMID: 26805780

Text-mined citations for rs863225087 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025