Submissions for variant NM_021971.4(GMPPB):c.79G>C (p.Asp27His)

gnomAD frequency: 0.00054  dbSNP: rs142336618

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000444697	SCV000518724	pathogenic	not provided	2021-12-20	criteria provided, single submitter	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)
Invitae	RCV000533184	SCV000653758	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14; Autosomal recessive limb-girdle muscular dystrophy type 2T	2024-01-08	criteria provided, single submitter	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). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000610921	SCV000712246	pathogenic	Muscular dystrophy	2017-03-17	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV000533184	SCV000894324	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14; Autosomal recessive limb-girdle muscular dystrophy type 2T	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000444697	SCV001246203	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	GMPPB: PM3:Very Strong, PM2:Supporting, PP1, PP4
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000054440	SCV001368633	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T	2018-12-04	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000444697	SCV001447196	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331794	SCV001523913	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14	2019-08-27	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000444697	SCV002018488	likely pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000444697	SCV002064426	pathogenic	not provided	2018-07-20	criteria provided, single submitter	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).
MGZ Medical Genetics Center	RCV000054440	SCV002580186	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T	2022-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513711	SCV003705965	pathogenic	Inborn genetic diseases	2022-10-25	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323382	SCV004029080	pathogenic	GMPPB-Related Disorders	2023-07-18	criteria provided, single submitter	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003388824	SCV004100758	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14	2023-10-20	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3_SUP,PP1; Identified as compund heterozygous with NM_021971.4:c.860G>A
PreventionGenetics, part of Exact Sciences	RCV003421962	SCV004116578	pathogenic	GMPPB-related condition	2024-01-15	criteria provided, single submitter	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.
OMIM	RCV000054440	SCV000082917	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T	2013-07-11	no assertion criteria provided	literature only