rs137852892

Positions:

• chr3-81646466-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000158.4(GBE1):​c.708G>C​(p.Gln236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,598,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.613

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

GBE1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 3-81646466-C-G is Pathogenic according to our data. Variant chr3-81646466-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81646466-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBE1	NM_000158.4	c.708G>C	p.Gln236His	missense_variant	6/16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.836G>C		non_coding_transcript_exon_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.708G>C	p.Gln236His	missense_variant	6/16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1	c.585G>C	p.Gln195His	missense_variant	6/16	2		ENSP00000419638.1
GBE1	ENST00000498468.1	n.258G>C		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000208 AC: 5 AN: 240712 Hom.: 0 AF XY: 0.0000306 AC XY: 4 AN XY: 130586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000700

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000207 AC: 30 AN: 1446064 Hom.: 0 Cov.: 27 AF XY: 0.0000236 AC XY: 17 AN XY: 719216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000218

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type IV Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 12, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 14, 2022	Variant summary: GBE1 c.708G>C (p.Gln236His) results in a non-conservative amino acid change located in the catalytic domain (IPR006047) 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 2.1e-05 in 240712 control chromosomes (i.e. 5 heterozygous carriers) in the gnomAD database. The variant, c.708G>C, has been reported in the literature in at least 3 compound heterozygous individuals affected with Glycogen Storage Disease, Type IV (Burrow_2006, Malfatti_2016, Ravenscroft_2021), and in two of these cases biochemical- or electron microscopy studies confirmed the diagnosis in patient derived samples (Burrow_2006, Malfatti_2016). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 05, 2023	The p.Gln236His variant in GBE1 has been reported in 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 16528737, 27546458, 33060286, 37598009) and has been identified in 0.003% (3/88322) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852892). 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, 2 were compound heterozygotes that carried a reported pathogenic variant in trans or with unknown phase which increases the likelihood that the p.Gln236His variant is pathogenic (VariationID: 208584; PMID: 33060286, 37598009). This variant has also been reported in ClinVar (Variation ID#: 2790) and has been interpreted as pathogenic by OMIM and Invitae, and likely pathogenic by Nilou-Genome Lab, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), MGZ Medical Genetics Center, GeneDx, and PreventionGenetics (PreventionGenetics). 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: 16528737). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive GSD IV. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3_strong, PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -

Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2006

- -

GBE1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2023

The GBE1 c.708G>C variant is predicted to result in the amino acid substitution p.Gln236His. This variant has been reported in the compound heterozygous states in individuals with glycogen storage disease type 4 (Burrow et al. 2006. PubMed ID: 16528737; Malfatti et al. 2016. PubMed ID: 27546458; Table S2, Ravenscroft et al. 2020. PubMed ID: 33060286; Table 1, Magoulas et al. 2012. PubMed ID: 22305237). This variant is reported in 0.0070% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81695617-C-G). This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2021

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: 31589614, 16528737, 27546458) -

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 236 of the GBE1 protein (p.Gln236His). This variant is present in population databases (rs137852892, gnomAD 0.007%). This missense change has been observed in individual(s) with GBE1-related conditions (PMID: 16528737, 27546458, 33060286). 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: 2790). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.86		Gain of sheet (P = 0.1945);.;
MVP		0.97
MPC		0.23
ClinPred		0.98	D
GERP RS		1.6
Varity_R		0.97
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852892; hg19: chr3-81695617;