rs142908436

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_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. R287L) has been classified as 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-49722056-C-A is described in Lovd as [Pathogenic].

PP5

Variant 3-49722057-G-A is Pathogenic according to our data. Variant chr3-49722057-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 225925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49722057-G-A is described in Lovd as [Pathogenic]. Variant chr3-49722057-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-49722057-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMPPB	NM_021971.4 linkuse as main transcript	c.859C>T	p.Arg287Trp	missense_variant	8/9	ENST00000308388.7	NP_068806.2
GMPPB	NM_013334.4 linkuse as main transcript	c.859C>T	p.Arg287Trp	missense_variant	8/8		NP_037466.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7 linkuse as main transcript	c.859C>T	p.Arg287Trp	missense_variant	8/9	1	NM_021971.4	ENSP00000311130	P1	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

GnomAD3 exomes

AF:

0.000104

AC:

AN:

249976

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

135310

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000133

Gnomad4 NFE exome

AF:

0.000144

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2020	PS3, PS4_moderate, PM2, PM3, PM5, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2024	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) -

Muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 11, 2020

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

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). 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 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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 25, 2018

- -

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

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

MutationTaster

Benign

0.99

D;D;D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over