rs142908436

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM5PP5_Very_Strong

The NM_021971.4(GMPPB):c.859C>T(p.Arg287Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,613,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R287Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

GMPPB
NM_021971.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.71

Publications

15 publications found

Variant links:

Genes affected

GMPPB (HGNC:22932): (GDP-mannose pyrophosphorylase B) This gene is thought to encode a GDP-mannose pyrophosphorylase. The encoded protein catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, a reaction involved in the production of N-linked oligosaccharides. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2009]

GMPPB Gene-Disease associations (from GenCC):

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
myopathy caused by variation in GMPPB
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2T
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
congenital myasthenic syndrome
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
congenital muscular dystrophy with cerebellar involvement
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital myasthenic syndromes with glycosylation defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscle-eye-brain disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GMPPB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-49722056-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 60545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 3-49722057-G-A is Pathogenic according to our data. Variant chr3-49722057-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 225925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPB	NM_021971.4 link	c.859C>T	p.Arg287Trp	missense_variant	Exon 8 of 9	ENST00000308388.7	NP_068806.2	Q9Y5P6-1
GMPPB	NM_013334.4 link	c.859C>T	p.Arg287Trp	missense_variant	Exon 8 of 8		NP_037466.3	Q9Y5P6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7 link	c.859C>T	p.Arg287Trp	missense_variant	Exon 8 of 9	1	NM_021971.4	ENSP00000311130.6		Q9Y5P6-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

249976

AF XY:

0.0000961

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

173

AN:

1461234

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000133

AC:

AN:

52790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000144

AC:

160

AN:

1111998

Other (OTH)

AF:

0.0000828

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000101

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 21, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PS4_moderate, PM2, PM3, PM5, PP4 -

May 19, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate decreased protein expression and increased propensity to form punctate aggregates (PMID: 26133662); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27147698, 30684953, 28433477, 27766311, 26133662, 26310427, 27874200, 30060766, 28478914, 29437916, 32115343, 31980526, 32528171, 37273706, 35006422, 38544359) -

Dec 04, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Muscular dystrophy

Pathogenic:1

Mar 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg287Trp variant in GMPPB has been reported in >10 individuals with limb-girdle muscular dystrophy (Jensen 2015, Oestergaard 2016, Montagnese 2016, Balcin 2017, Sarkozy 2018, Johnson 2018) or congenital myasthenic syndrome (Belaya 2015), all of whom were compound heterozygous with a pathogenic variant on the other allele. This variant also segregated with disease in 1 affected family member (Oestergaard 2016). It was also identified in 0.01% (25/127816) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Another missense variant at this same codon, p.Arg287Gln, has been reported in multiple individuals with features of limb-girdle and other muscular dystrophies (Sun 2019). In vitro functional studies provide some evidence that the p.Arg287Trp variant may impact protein stability (Belaya 2015); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy in an autosomal recessive manner based upon the presence of the variant in trans with a pathogenic variant in affected individuals, the overall low general population frequency, and a different pathogenic missense at the same position. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PM5, PP1. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;C3809221:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;C4518000:Autosomal recessive limb-girdle muscular dystrophy type 2T

Pathogenic:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 287 of the GMPPB protein (p.Arg287Trp). This variant is present in population databases (rs142908436, gnomAD 0.02%). This missense change has been observed in individuals with GMPPB-related disease (PMID: 26133662, 27766311, 27874200, 28478914). ClinVar contains an entry for this variant (Variation ID: 225925). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GMPPB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GMPPB function (PMID: 26133662). This variant disrupts the p.Arg287 amino acid residue in GMPPB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24780531, 26133662). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2T

Pathogenic:1

Sep 25, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

.;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

0.050

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

4.7

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.74

MVP

0.87

MPC

1.4

ClinPred

0.65

GERP RS

4.5

Varity_R

0.75

gMVP

0.82

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over