Submissions for variant NM_000158.4(GBE1):c.1229T>G (p.Ile410Arg)

gnomAD frequency: 0.00001  dbSNP: rs771405370

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001829303	SCV002097102	uncertain significance	Glycogen storage disease, type IV	2022-01-27	criteria provided, single submitter	curation	The p.Ile410Arg variant in GBE1 has been reported in 2 individuals with glycogen storage disease type IV (GSD IV) (PMID: 33897756, Liao et al.) and has been identified in 0.03% (6/19242) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs771405370). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the 2 affected individuals, both were compound heterozygotes that carried variants of uncertain significance in trans, which increases the likelihood that the p.Ile410Arg variant is pathogenic (PMID: 33897756, Liao et al.). 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, the clinical significance of the p.Ile410Arg variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331213	SCV004037857	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: GBE1 c.1229T>G (p.Ile410Arg) results in a non-conservative amino acid change located in the glycosyl hydrolase, family 13, catalytic domain (IPR006047) 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 2.1e-05 in 243764 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1229T>G has been reported in the literature as a compound heterozygous genotype in an individual affected with Glycogen Storage Disease, Type IV (GSD IV) (Liao_2020, no PMID) and also in a case of fetal hydrops where GSD IV was suspected and the parents had a prior fetal hydrops-affected pregnancy (Zhou_2021, PMID: 33897756). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004529022	SCV004106008	likely pathogenic	GBE1-related disorder	2023-06-22	criteria provided, single submitter	clinical testing	The GBE1 c.1229T>G variant is predicted to result in the amino acid substitution p.Ile410Arg. This variant was reported in the compound heterozygous state in a fetus with Hydrops fetalis, nonimmune (Zhou et al. 2021. PubMed ID: 33897756). It's also been detected, in the compound heterozygous state, in a neonate with clinical and biochemical features consistent with GSD IV severe neuromuscular type (Internal data, PreventionGenetics). This variant is reported in 0.031% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81640195-A-C). This variant is interpreted as likely pathogenic.