rs142336618

Positions:

chr3-49723648-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4

The NM_021971.4(GMPPB):c.79G>C(p.Asp27His) variant causes a missense change. The variant allele was found at a frequency of 0.000951 in 1,582,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

GMPPB
NM_021971.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 5.53

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.

PM1

In a strand (size 6) in uniprot entity GMPPB_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_021971.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-49723648-C-G is Pathogenic according to our data. Variant chr3-49723648-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49723648-C-G is described in Lovd as [Likely_pathogenic]. Variant chr3-49723648-C-G is described in Lovd as [Likely_pathogenic]. Variant chr3-49723648-C-G is described in Lovd as [Pathogenic]. Variant chr3-49723648-C-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.31139874). . 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.79G>C	p.Asp27His	missense_variant	1/9	ENST00000308388.7	NP_068806.2	Q9Y5P6-1
GMPPB	NM_013334.4 linkuse as main transcript	c.79G>C	p.Asp27His	missense_variant	1/8		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.79G>C	p.Asp27His	missense_variant	1/9	1	NM_021971.4	ENSP00000311130.6		Q9Y5P6-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000564

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000896

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000704

AC:

157

AN:

222868

Hom.:

AF XY:

0.000742

AC XY:

AN XY:

119890

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00122

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.000997

AC:

1427

AN:

1430598

Hom.:

Cov.:

AF XY:

0.000919

AC XY:

652

AN XY:

709342

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.0000491

Gnomad4 ASJ exome

AF:

0.0000422

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00138

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.000407

GnomAD4 genome

AF:

0.000519

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000564

Gnomad4 NFE

AF:

0.000896

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000461

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000816

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	GMPPB: PM3:Very Strong, PM2:Supporting, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2018	DNA sequence analysis of the GMPPB gene demonstrated a sequence change, c.79G>C, that results in an amino acid change, p.Asp27His. This sequence change has been described in the EXAC database with a low population frequency of 0.08% (dbSNP rs142336618). The p.Asp27His change affects a poorly conserved amino acid residue located in a domain of the GMPPB protein that is known to be functional. This pathogenic sequence change has previously been described in a multiple patients with GMPPB-related dystroglycanopathy, and some genotype-phenotype correlation studies suggest that this variant may typically be associated with a limb-girdle muscular dystrophy phenotype (Jensen et al., 2015. Hum Mutat 36(12): 1159-63; Cabrera-Serrano et al., 2015. Brain 138:836-44). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2021	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: 34106991, 28433477, 28478914, 28456886, 27259053, 26436962, 23768512, 26310427, 25770200, 25681410, 26133662, 27766311, 27874200, 29363764, 29437916, 27535533, 32528171) -

Autosomal recessive limb-girdle muscular dystrophy type 2T

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 04, 2018	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -

GMPPB-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2023	Variant summary: GMPPB c.79G>C (p.Asp27His) results in a non-conservative amino acid change located in the Nucleotidyl transferase domain (IPR005835) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 222868 control chromosomes in the gnomAD database, including 1 homozygotes. c.79G>C has been reported in the literature in multiple compound heterozygous individuals affected with GMPPB-Related Limb Girdle Muscular Dystropy (Cabrera-Serrano_2015, Carrs_2013, Jensen_2015) and shown to segregate with disease in multiple families. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a 50% decrease in enzyme activity when compared to Wildtype (Liu_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25681410, 23768512, 26310427, 35006422). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 15, 2024	The GMPPB c.79G>C variant is predicted to result in the amino acid substitution p.Asp27His. This variant has been reported in the compound heterozygous state in many unrelated patients with GMPPB-related disease (Carss et al. 2013. PubMed ID: 23768512; Belaya et al. 2015. PubMed ID: 26133662; Jensen et al. 2015. PubMed ID: 26310427). In addition, at PreventionGenetics we have observed this variant in the compound heterozygous state with another pathogenic variant in several patients (internal data). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret c.79G>C (p.Asp27His) as pathogenic. -

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:2

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 08, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 27 of the GMPPB protein (p.Asp27His). This variant is present in population databases (rs142336618, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy, congenital myasthenic syndrome, and/or muscle weakness with intellectual disability and epilepsy (PMID: 23768512, 25681410, 25770200, 26133662, 26310427). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60546). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on GMPPB function (PMID: 23768512). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.79G>C (p.D27H) alteration is located in exon 1 (coding exon 1) of the GMPPB gene. This alteration results from a G to C substitution at nucleotide position 79, causing the aspartic acid (D) at amino acid position 27 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.066% (169/254268) total alleles studied. The highest observed frequency was 0.117% (137/117422) of European (non-Finnish) alleles. This variant segregates with disease in multiple families and has been detected in the homozygous state or in conjunction with a second GMPPB variant in multiple individuals with clinical features of GMPPB-related dystroglycanopathies (Carss, 2013; Bharucha-Goebel, 2015; Cabrera-Serrano, 2015; Jensen, 2015; Belaya, 2015; Oestergaard, 2016; Montagnese, 2017; Balcin, 2017; Astrea, 2018; Sarkozy, 2018; Gonzalez-Perez, 2020; Babi Boovi, 2021). This amino acid position is not well conserved in available vertebrate species. Functional studies indicate this alteration impairs enzymatic activity of GMPPB (Liu, 2021). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 17, 2017

The p.Asp27His variant in GMPPB has been reported in the homozygous or compound heterozygous state in at least 15 individuals with muscular dystrophy, and segre gated with disease in 5 affected relatives from 5 families (Carss 2013, Belaya 2 015, Cabrera-Serrano 2015, Jensen 2015, Montagnese 2016, Oestergaard 2016). It w as also identified in 0.1% (89/64040) of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142336618). Thi s frequency is low enough that it may be consistent with a recessive carrier fre quency, thoughthere is limited prevalence data for the associated disease. In ad dition, the available evidence suggests that it may be associated with a milder course of disease (Jensen 2015, Montagnese 2016). In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy in a n autosomal recessive manner. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 20, 2023

Criteria applied: PM3_VSTR,PS3_SUP,PP1; Identified as compund heterozygous with NM_021971.4:c.860G>A -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 27, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;.;D

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.3

L;L;L

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.024

D;D;D

Sift4G

Benign

0.080

T;D;T

Polyphen

0.089

B;D;B

Vest4

0.78

MVP

0.93

MPC

1.4

ClinPred

0.57

GERP RS

4.8

Varity_R

0.81

gMVP

0.62

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