Submissions for variant NM_000158.4(GBE1):c.1883A>G (p.His628Arg)

gnomAD frequency: 0.00001  dbSNP: rs137852891

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000056098	SCV000915065	likely pathogenic	Glycogen storage disease, type IV	2024-09-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092351	SCV001248810	pathogenic	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056098	SCV002041497	likely pathogenic	Glycogen storage disease, type IV	2021-11-07	criteria provided, single submitter	clinical testing	Variant summary: GBE1 c.1883A>G (p.His628Arg) results in a non-conservative amino acid change located in the Alpha-amylase/branching enzyme, C-terminal all beta domain (IPR006048) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247212 control chromosomes. c.1883A>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease, Type IV (example, Bruno_2004, Kuhn_2016, Yubero_2016, Derks_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although some of the affected compound heterozygous individuals mentioned above were reported to have a deficiency of branching enzyme activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000056098	SCV002097078	likely pathogenic	Glycogen storage disease, type IV	2022-01-27	criteria provided, single submitter	curation	The p.His628Arg variant in GBE1 has been reported in at least 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 15452297, 26886200, 33332610, 33473341) and has been identified in 0.0009% (1/112290) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852891). 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 likely pathogenic variant in trans, and 2 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the p.His628Arg variant is pathogenic (VariationID: 208584, 2781; PMID: 26886200, 33332610, 15452297). This variant has also been reported in ClinVar (Variation ID#: 2788) and has been interpreted as pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, OMIM, and GeneReviews and as a variant of uncertain significance by Illumina Clinical Services Laboratory (Illumina). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual compound heterozygous for this variant is highly specific for GSD IV based on strict biochemical investigations consistent with disease (PMID: 15452297). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for GSD IV. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting, PP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851596	SCV002235555	pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 628 of the GBE1 protein (p.His628Arg). This variant is present in population databases (rs137852891, gnomAD 0.0009%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 15452297, 26886200, 27243974, 33332610). 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: 2788). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBE1 protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000056098	SCV004198707	likely pathogenic	Glycogen storage disease, type IV	2024-02-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001092351	SCV005201959	likely pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 15452297, 17915577, 26199317, 33473341, 29379554, 20058079, 33332610, 22305237, 27243974, 26886200)
OMIM	RCV000002922	SCV000023080	pathogenic	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form	2004-09-28	no assertion criteria provided	literature only
GeneReviews	RCV000056098	SCV000087170	pathologic	Glycogen storage disease, type IV	2009-04-02	no assertion criteria provided	curation	Converted during submission to Pathogenic.