3-49721835-C-T

Position:

chr3-49721835-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_021971.4(GMPPB):c.1000G>A(p.Asp334Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

GMPPB
NM_021971.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 7.81

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-49721835-C-T is Pathogenic according to our data. Variant chr3-49721835-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49721835-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-49721835-C-T is described in Lovd as [Pathogenic]. Variant chr3-49721835-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMPPB	NM_021971.4 linkuse as main transcript	c.1000G>A	p.Asp334Asn	missense_variant	9/9	ENST00000308388.7	NP_068806.2	Q9Y5P6-1
GMPPB	NM_013334.4 linkuse as main transcript	c.1081G>A	p.Asp361Asn	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.1000G>A	p.Asp334Asn	missense_variant	9/9	1	NM_021971.4	ENSP00000311130.6		Q9Y5P6-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251044

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461416

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000896

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2T

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.1000G>A (p.Asp334Asn) in GMPPB gene has been reported in the homozygous state in an individual affected myopathy and it has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with congenital muscular dystrophy(Carss KJ et.al.,2013). Experimental studies have shown that this missense change disrupts the normal cellular localization of GDP-mannose pyrophorphorylase and leads to a reduction of glycosylated alpha-dystroglycan(Stevens E et.al.,2013). The p.Asp334Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.007568% is reported in gnomAD. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The amino acid Asp at position 334 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asp334Asn in GMPPB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Dr.Nikuei Genetic Center	May 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	This variant is present in one similarly affected individual in a homozygous state in our in-house exome data. In-silico analysis tools (REVEL, CADD_phred, GERP, MutationTaster) are consistent in predicting the variant to impair GMPPB protein function. The variant c.1000G>A has been reported as pathogenic/likely pathogenic by 12 submitters to the ClinVar database (ClinVar id. 60540). This missense variant has been observed in individuals with muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 (Polavarapu et al., 2021). Bi-allelic variants in GMPPB have been reported to cause muscular dystrophy-dystroglycanopathy (type A, 14; type B, 14; type C, 14). The clinical features observed in her are in concordance with muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14. Thus, the above-mentioned variant in homozygous state is interpreted to be the cause for the condition observed in her. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2021	Published functional studies demonstrate a damaging effect: abnormal subcellular localization (Carss et al., 2013); 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: 26133662, 28456886, 23768512, 29437916, 23894383, 33060286) -

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

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
Uncertain significance, flagged submission	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

GMPPB-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 10, 2023

Variant summary: GMPPB c.1081G>A (p.Asp361Asn), also referred to as c.1000G>A (p.Asp334Asn) in the literature, results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251044 control chromosomes, found exclusively within the South Asian subpopulation at a frequency of 0.00062 in the gnomAD database. c.1081G>A has been reported in the literature as a compound heterozygous genotype in at least two individuals affected with congenital muscular dystrophy who have subsequently been cited in other publications (e.g. Carrs_2013, Stevens_2013, Belaya_2015) and in the homozygous state in 12 individuals from 7 different families in which the variant segregated with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype (Polavarapu_2021). In all cases, the affected individuals were of South Asian descent, and it has been suggested the variant may be a common founder variant in individuals of South Indian ancestry (Polavarapu_2021). 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 and found the variant formed aggregates in the cytoplasm, whereas the wild type GMPPB protein is soluble, however, this study did not evalute the impact of the variant on enzyme activity (e.g. Carrs_2013). The following publications have been ascertained in the context of this evaluation (PMID: 26133662, 23768512, 34333724, 23894383). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2020

The c.1081G>A (p.D361N) alteration is located in exon 8 (coding exon 8) of the GMPPB gene. This alteration results from a G to A substitution at nucleotide position 1081, causing the aspartic acid (D) at amino acid position 361 to be replaced by an asparagine (N). Based on data from the Genome Aggregation Database (gnomAD) database, the GMPPB c.1081G>A alteration was observed in 0.01% (19/251044) of total alleles studied, with a frequency of 0.06% (19/30616) in the South Asian subpopulation. This alteration has been reported in conjunction with a second disease-causing allele in multiple patients with congenital/early-onset muscular dystrophy and intellectual disability (Stevens, 2013; Belaya, 2015; Sarkozy, 2018). This amino acid position is highly conserved in available vertebrate species. Functional analysis revealed that this alteration causes the protein to localize differently and aggregate as compared to wild-type protein (Carss, 2013). Additionally, analysis of patient fibroblasts revealed a reduction in glycosylated alpha-dystroglycan (Stevens, 2013). The p.D361N alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 334 of the GMPPB protein (p.Asp334Asn). This variant is present in population databases (rs397509422, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of GMPPB-related conditions (PMID: 23768512, 26133662; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 60540). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GMPPB function (PMID: 23768512). For these reasons, this variant has been 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

0.27

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.5

M;.;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Uncertain

0.47

Sift

Benign

0.077

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.21

B;P;B

Vest4

0.73

MutPred

0.58

Loss of phosphorylation at Y337 (P = 0.0728);.;Loss of phosphorylation at Y337 (P = 0.0728);

MVP

0.85

MPC

1.5

ClinPred

0.90

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.46

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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