Submissions for variant NM_000158.4(GBE1):c.293T>G (p.Val98Gly)

gnomAD frequency: 0.00003  dbSNP: rs775486403

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001829310	SCV002097126	uncertain significance	Adult polyglucosan body disease	2022-01-27	criteria provided, single submitter	curation	The p.Val98Gly variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with adult polyglucosan body disease (APBD) (PMID: 34999962) and has been identified in 0.001% (1/103112) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs775486403). 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. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val98Gly variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002542782	SCV003465626	uncertain significance	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2022-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 98 of the GBE1 protein (p.Val98Gly). This variant is present in population databases (rs775486403, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with GBE1-related conditions. 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) performed at Invitae indicates that this missense variant is not expected to disrupt GBE1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003333181	SCV004040828	likely pathogenic	Glycogen storage disease, type IV	2023-06-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003481134	SCV004226127	uncertain significance	not provided	2022-10-31	criteria provided, single submitter	clinical testing	PP4, PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690142	SCV005185679	uncertain significance	not specified	2024-05-16	criteria provided, single submitter	clinical testing	Variant summary: GBE1 c.293T>G (p.Val98Gly) results in a non-conservative amino acid change located in the Glycoside hydrolase, family 13, N-terminal domain (IPR004193) 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 4.4e-06 in 225816 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.293T>G has been reported in the literature in one individual affected with Adult polyglucosan body disease (Zebhauser_2022). 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. The following publication has been ascertained in the context of this evaluation (PMID: 34999962). ClinVar contains an entry for this variant (Variation ID: 1341396). Based on the evidence outlined above, the variant was classified as uncertain significance.