NM_021971.4(GMPPB):c.860G>A (p.Arg287Gln) AND Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 17, 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:: RCV000054439.10

Allele description [Variation Report for NM_021971.4(GMPPB):c.860G>A (p.Arg287Gln)]

NM_021971.4(GMPPB):c.860G>A (p.Arg287Gln)

Gene:

GMPPB:GDP-mannose pyrophosphorylase B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_021971.4(GMPPB):c.860G>A (p.Arg287Gln)

HGVS:

NC_000003.12:g.49722056C>T
NG_011603.1:g.37500C>T
NG_033731.1:g.6919G>A
NG_033731.2:g.6919G>A
NM_013334.4:c.860G>A
NM_021971.4:c.860G>AMANE SELECT
NP_037466.2:p.Arg287Gln
NP_037466.3:p.Arg287Gln
NP_068806.2:p.Arg287Gln
NC_000003.11:g.49759489C>T
NM_013334.2:c.860G>A
NM_013334.3:c.860G>A
NM_021971.1:c.860G>A
NM_021971.2:c.860G>A
NM_021971.4:c.860G>A
Q9Y5P6:p.Arg287Gln

Protein change:

R287Q; ARG287GLN

Links:

UniProtKB: Q9Y5P6#VAR_070146; OMIM: 615320.0006; dbSNP: rs202160208

NCBI 1000 Genomes Browser:

rs202160208

Molecular consequence:

NM_013334.4:c.860G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021971.4:c.860G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (MDDGB14)
Synonyms:: MUSCULAR DYSTROPHY, CONGENITAL, GMPPB-RELATED; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B14; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 14
Identifiers:: MONDO: MONDO:0014141; MedGen: C3809221; OMIM: 615351

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082916	OMIM	no assertion criteria provided	Pathogenic (Jul 11, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002097271	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 30257713, 29437916, 28877744, 27766311, 26310427, 26133662, 25741868
SCV005086529	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30684953, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000082916

OMIM

no assertion criteria provided

Pathogenic
(Jul 11, 2013)

germline

literature only

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

SCV002097271

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 14, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV005086529

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan.

Carss KJ, Stevens E, Foley AR, Cirak S, Riemersma M, Torelli S, Hoischen A, Willer T, van Scherpenzeel M, Moore SA, Messina S, Bertini E, Bönnemann CG, Abdenur JE, Grosmann CM, Kesari A, Punetha J, Quinlivan R, Waddell LB, Young HK, Wraige E, Yau S, et al.

Am J Hum Genet. 2013 Jul 11;93(1):29-41. doi: 10.1016/j.ajhg.2013.05.009. Epub 2013 Jun 13.

PubMed [citation]

PMID:: 23768512
PMCID:: PMC3710768

Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study.

Astrea G, Romano A, Angelini C, Antozzi CG, Barresi R, Battini R, Battisti C, Bertini E, Bruno C, Cassandrini D, Fanin M, Fattori F, Fiorillo C, Guerrini R, Maggi L, Mercuri E, Morani F, Mora M, Moro F, Pezzini I, Picillo E, Pinelli M, et al.

Orphanet J Rare Dis. 2018 Sep 26;13(1):170. doi: 10.1186/s13023-018-0863-x.

PubMed [citation]

PMID:: 30257713
PMCID:: PMC6158856

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000082916.4

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

Description

For discussion of the arg287-to-gln (R287Q) mutation in the GMPPB gene that was found in compound heterozygous state in 2 patients with congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development type B14 (MDDGB14; 615351) by Carss et al. (2013), see 615320.0005.

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

From DASA, SCV002097271.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26133662) - PS3_supporting. The c.860G>A;p.(Arg287Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 30257713; 29437916; 28877744; 27766311; 26310427; 26133662) - PS4. The variant is present at low allele frequencies population databases (rs202160208 - gnomAD 0.001905%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg287Gln) was detected in trans with a pathogenic variant (PMID: 30257713; 29437916; 28877744; 26310427; 26133662) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 225925) - PM5. Multiple lines of computational evidence suggest no impact on gene orgene product - BP4. In summary, the currently available evidence indicates that the variant is pathogenic.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086529.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 (MIM#615350), muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 (MIM#615351), and muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 (MIM#615352). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (78 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (28 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in compound heterozygous individuals with limb girdle muscular dystrophy (MD), congenital MD with intellectual disability or MD dystroglycanopathy (PMID: 30684953, ClinVar). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Apr 13, 2025

ClinVar

Relating variation to medicine