rs142336618

Variant names:

• chr3-49723648-C-G
• rs142336618
• NM_021971.4:c.79G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 5.53
• Publications: 22 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_021971.4
• PP5: Variant 3-49723648-C-G is Pathogenic according to our data. Variant chr3-49723648-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 60546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
GMPPB	NM_021971.4	c.79G>C	p.Asp27His	missense_variant	Exon 1 of 9	ENST00000308388.7	NP_068806.2
GMPPB	NM_013334.4	c.79G>C	p.Asp27His	missense_variant	Exon 1 of 8		NP_037466.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7	c.79G>C	p.Asp27His	missense_variant	Exon 1 of 9	1	NM_021971.4	ENSP00000311130.6

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152266 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000704 AC: 157 AN: 222868 AF XY: 0.000742

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 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.: 1 Cov.: 33 AF XY: 0.000919 AC XY: 652 AN XY: 709342

African (AFR) AF: 0.000123 AC: 4 AN: 32626

American (AMR) AF: 0.0000491 AC: 2 AN: 40730

Ashkenazi Jewish (ASJ) AF: 0.0000422 AC: 1 AN: 23704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 81494

European-Finnish (FIN) AF: 0.00138 AC: 70 AN: 50906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00121 AC: 1326 AN: 1097036

Other (OTH) AF: 0.000407 AC: 24 AN: 58990

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74384

African (AFR) AF: 0.000217 AC: 9 AN: 41474

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000896 AC: 61 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000461 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000816 AC: 99

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GMPPB: PM3:Very Strong, PM2:Supporting, PP1 -

Dec 20, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2024

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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

Jun 09, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2T Pathogenic:3

Jul 11, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 04, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3. -

Jul 15, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GMPPB-related disorder Pathogenic:2

Jan 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jul 18, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Pathogenic:1

Oct 25, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-dystroglycanopathy (congenital with brain and eye anomalies), type A14 Pathogenic:1

Oct 20, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Muscular dystrophy Pathogenic:1

Mar 17, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 intellectual disability), type B14 Pathogenic:1

Aug 27, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.3	L;L;L
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
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	D
GERP RS		4.8
PromoterAI		-0.059	Neutral
Varity_R		0.81
gMVP		0.62
Mutation Taster		=44/56	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs142336618; hg19: chr3-49761081;