ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.1544G>A (p.Arg515His)

gnomAD frequency: 0.00005  dbSNP: rs201958741
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000519980 SCV000342181 pathogenic not provided 2016-06-03 criteria provided, single submitter clinical testing
GeneDx RCV000519980 SCV000616730 likely pathogenic not provided 2017-07-17 criteria provided, single submitter clinical testing The R515H variant in the GBE1 gene has previously been reported in association with adult polyglucosan body disease in individuals who were homozygous for R515H or heterozygous for R515H and another variant in GBE1 (Sindern et al., 2003; Paradas et al., 2014). The R515H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R515H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R515C) has also been reported in the Human Gene Mutation Database in association with glycogen storage disorder type IV (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000692455 SCV000820280 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 515 of the GBE1 protein (p.Arg515His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201958741, ExAC 0.01%). This variant has been observed as homozygous or in combination with another GBE1 variant in individuals affected with adult polyglucosan body disease or glycogen storage disease IV (PMID: 10762170, 24248152, Invitae). In addition, this variant has been observed on the opposite chromosome (in trans) from a pathogenic GBE1 variant in an individual affected with branching enzyme deficiency (PMID: 24248152). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 180651). 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: Not Available; PolyPhen-2: Probably Damaging; Align-GVGD: Not Available). This variant disrupts the p.Arg515 amino acid residue in GBE1. Other variant(s) that disrupt this residue have been observed in individuals with GBE1-related conditions (PMID: 8613547, 20058079), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001826858 SCV002097093 likely pathogenic Adult polyglucosan body disease 2022-01-27 criteria provided, single submitter curation The p.Arg515His variant in GBE1 has been reported in 4 individuals with adult polyglucosan body disease (APBD) (PMID: 10762170, 24248152, 31815882) and has been identified in 0.008% (2/23806) of African/African American chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP ID: rs201958741). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 4 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variants in trans, 1 was a homozygote, and 2 were compound heterozygotes that carried variants of uncertain significance in trans, which increases the likelihood that the p.Arg515His variant is pathogenic (VariationID: 2782; PMID: 10762170, 24248152, 31815882). This variant has also been reported in ClinVar (Variation ID#: 180651) and has been interpreted as pathogenic or likely pathogenic by Invitae, OMIM, GeneDx, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), and Natera. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for APBD. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting (Richards 2015).
Mendelics RCV001275349 SCV002516451 pathogenic Glycogen storage disease, type IV 2022-05-04 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252009 SCV002522984 likely pathogenic See cases 2022-01-12 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM2, PM3, PP3
OMIM RCV000157612 SCV000207421 pathogenic Adult polyglucosan body neuropathy 2000-04-01 no assertion criteria provided literature only
Natera, Inc. RCV001275349 SCV001460446 likely pathogenic Glycogen storage disease, type IV 2020-09-16 no assertion criteria provided clinical testing

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