ClinVar Miner

Submissions for variant NM_021971.4(GMPPB):c.553C>T (p.Arg185Cys)

gnomAD frequency: 0.00001  dbSNP: rs397509425
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000200261 SCV000255381 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 2014-01-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000503216 SCV000595011 likely pathogenic Muscular dystrophy-dystroglycanopathy 2017-05-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623944 SCV000742877 pathogenic Inborn genetic diseases 2017-08-07 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000503216 SCV001445862 pathogenic Muscular dystrophy-dystroglycanopathy 2019-05-29 criteria provided, single submitter clinical testing This variant has been previously reported as a homozygous change in 6 patients with hypotonia, muscle weakness, cataracts, and elevated serum creatine kinase (PMID: 23768512, 29054425). Functional studies have shown reduced alpha-dystroglycan glycosylation in muscle and fibroblasts of individuals with this variant (PMID: 23768512). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0036% (9/250,734) and thus is presumed to be rare. The c.553C>T (p.Arg185Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.553C>T (p.Arg185Cys) variant is classified as Pathogenic.
Revvity Omics, Revvity RCV001781385 SCV002018486 likely pathogenic not provided 2022-09-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000200261 SCV002296015 likely 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 2022-08-16 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 185 of the GMPPB protein (p.Arg185Cys). This variant is present in population databases (rs397509425, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of GMPPB-related conditions (PMID: 23768512, 25326637, 30684953, 32403337, 32404165). ClinVar contains an entry for this variant (Variation ID: 60543). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GMPPB function (PMID: 23768512). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site.
OMIM RCV000054436 SCV000082913 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 2013-07-11 no assertion criteria provided literature only
OMIM RCV000054437 SCV000082914 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2T 2013-07-11 no assertion criteria provided literature only

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