Submissions for variant NM_021971.4(GMPPB):c.1000G>A (p.Asp334Asn)

dbSNP: rs397509422

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000651273	SCV000773124	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	2024-11-15	criteria provided, single submitter	clinical testing	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; internal data). 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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001836725	SCV000927088	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000054433	SCV001429989	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T	2017-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000788090	SCV001796948	pathogenic	not provided	2021-10-11	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000788090	SCV002024858	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513710	SCV003709698	likely pathogenic	Inborn genetic diseases	2020-12-31	criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000054433	SCV004047145	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T		criteria provided, single submitter	clinical testing	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 .
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004549480	SCV004122701	pathogenic	GMPPB-related disorder	2023-10-10	criteria provided, single submitter	clinical testing	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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000054433	SCV005381838	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T		criteria provided, single submitter	clinical testing	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.
OMIM	RCV000054432	SCV000082909	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14	2013-07-11	no assertion criteria provided	literature only
OMIM	RCV000054433	SCV000082910	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T	2013-07-11	no assertion criteria provided	literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000054432	SCV002053816	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14		flagged submission	clinical testing
Dr.Nikuei Genetic Center	RCV000054433	SCV005068163	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2T	2024-05-21	no assertion criteria provided	clinical testing