rs202160208

Positions:

chr3-49722056-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2PM5PP5_Very_StrongBP4

The NM_021971.4(GMPPB):c.860G>A(p.Arg287Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000179 in 1,613,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

GMPPB
NM_021971.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20U:1

Conservation

PhyloP100: 4.17

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:

GMPPB (HGNC:):

GMPPB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 3-49722056-C-T is Pathogenic according to our data. Variant chr3-49722056-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49722056-C-T is described in Lovd as [Pathogenic]. Variant chr3-49722056-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-49722056-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.014596343). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMPPB	NM_021971.4 linkuse as main transcript	c.860G>A	p.Arg287Gln	missense_variant	8/9	ENST00000308388.7	NP_068806.2	Q9Y5P6-1
GMPPB	NM_013334.4 linkuse as main transcript	c.860G>A	p.Arg287Gln	missense_variant	8/8		NP_037466.3	Q9Y5P6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7 linkuse as main transcript	c.860G>A	p.Arg287Gln	missense_variant	8/9	1	NM_021971.4	ENSP00000311130.6		Q9Y5P6-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000288

AC:

AN:

249958

Hom.:

AF XY:

0.000296

AC XY:

AN XY:

135314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000187

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1461260

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00536

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000755

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000191

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000555

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 20, 2021	BP4, PP1, PM3, PM5, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2024	Published functional studies demonstrate a damaging effect, as C2C12 myoblast cell lines transfected with R287Q showed abnormal subcellular localization of GMPPB resulting in cytoplasmic protein aggregates (PMID: 23768512); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34758253, 24780531, 23768512, 28456886, 28433477, 27766311, 28478914, 27874200, 30684953, 34426522, 35006422, 31980526, 26133662, 28554332, 34008892, 28877744, 26310427, 25681410) -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14

Pathogenic:3Uncertain:1

Uncertain significance, flagged submission	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 20, 2023	Criteria applied: PM3_VSTR,PM5,PS3_SUP,PM2_SUP; Identified as compund heterozygous with NM_021971.4:c.79G>C -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 -

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:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 287 of the GMPPB protein (p.Arg287Gln). This variant is present in population databases (rs202160208, gnomAD 0.5%). This missense change has been observed in individual(s) with congenital muscular dystrophy-dystroglycanopathy and congenital myasthenic syndrome (PMID: 24780531, 26133662). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60545). 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: 23768512). 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: 27766311, 27874200, 28478914). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 05, 2020	- -

Autosomal recessive limb-girdle muscular dystrophy type 2T

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PM2, PM5, PP2, PP5 -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.028%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23768512). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000060545) and a different missense change at the same codon (p.Arg287Trp / ClinVar ID: VCV000225925) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

GMPPB-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 26, 2023	Variant summary: GMPPB c.860G>A (p.Arg287Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 249958 control chromosomes (gnomAD). c.860G>A has been reported in the literature in multiple individuals affected with congenital muscular dystrophy/alpha-dystroglycanopathy, including at least one family in which it segregated with the disease phenotype (e.g. Carrs_2013, Raphael_2014, Jensen_2015). These data indicate that the variant is very likely to be associated with disease. Functional experiments have shown that the variant has approximately 50% activity compared to the WT protein in an enzymatic activity assay and in vitro, results in the formation of aggregates, affecting the cellular localization of the protein (e.g. Carrs_2013, Liu_2021). Twelve submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as either pathogenic (n=10) or likely pathogenic (n=1), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	May 16, 2024	The GMPPB c.860G>A variant is predicted to result in the amino acid substitution p.Arg287Gln. This variant has been reported in the compound heterozygous state in many unrelated individuals with GMPBB-related disorders (see for examples, Carss et al. 2013. PubMed ID: 23768512; Belaya et al. 2015. PubMed ID: 26133662; Jensen et al. 2015. PubMed ID: 26310427). This variant is reported in 0.42% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Given the evidence, we interpret c.860G>A (p.Arg287Gln) as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.860G>A (p.R287Q) alteration is located in coding exon 8 of the GMPPB gene. This alteration results from a G to A substitution at nucleotide position 860, causing the arginine (R) at amino acid position 287 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.028% (78/281352) total alleles studied. The highest observed frequency was 0.425% (44/10356) of Ashkenazi Jewish alleles. This variant has been reported in trans with a second alteration in the GMPPB gene in multiple individuals with clinical features of GMPPB-related dystroglycanopathies (Carss, 2013; Raphael, 2014; Belaya, 2015; Cabrera-Serrano, 2015; Jensen, 2015; Harris, 2017; Astrea, 2018; Sarkozy, 2018; Marinakis, 2021). In two families, both variants segregated with disease (Belaya, 2015; Raphael, 2014). In addition, this variant has been observed in homozygous individuals without clinical features of GMPPB-related dystroglycanopathies, suggesting it may be a mild allele (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. Functional studies indicate this alteration mildly impairs enzymatic activity of GMPPB compared to other pathogenic alterations (Liu, 2021). In another study, functional analysis demonstrated that the p.R287Q alteration aggregated in the cytoplasm in transfected cells as well as decreased glycosylation of α-dystroglycan in muscle biopsies; however, a later study found that this variant had no effect on protein expression levels (Belaya, 2015; Carss, 2013). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Abnormality of the musculature

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Uncertain

0.50

D;.;D

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.074

FATHMM_MKL

Benign

0.75

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.92

N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

0.14

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.94

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.80

MVP

0.76

MPC

0.64

ClinPred

0.031

GERP RS

4.0

Varity_R

0.10

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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