3-81535304-C-T

Position:

• chr3-81535304-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000158.4(GBE1):​c.1825G>A​(p.Glu609Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000454 in 1,609,352 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (1 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:5
• Conservation: PhyloP100: 5.68

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-81535304-C-T is Pathogenic according to our data. Variant chr3-81535304-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577677.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=3}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2476669). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBE1	NM_000158.4	c.1825G>A	p.Glu609Lys	missense_variant	14/16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.1953G>A		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.1825G>A	p.Glu609Lys	missense_variant	14/16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1	c.1702G>A	p.Glu568Lys	missense_variant	14/16	2		ENSP00000419638.1
GBE1	ENST00000484687.1	n.226G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 45 AN: 244706 Hom.: 0 AF XY: 0.000211 AC XY: 28 AN XY: 132812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00208

Gnomad SAS exome AF: 0.000203

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.0000432 AC: 63 AN: 1457218 Hom.: 1 Cov.: 31 AF XY: 0.0000552 AC XY: 40 AN XY: 724888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000110

ExAC AF: 0.000190 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type IV Pathogenic:2 Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM3_Strong+PP4+PP3 -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 27, 2022	The p.Glu609Lys variant in GBE1 has been reported in 3 individuals with glycogen storage disease type IV (GSD IV) (PMID: 32455116, 30228975) and has been identified in 0.2% (39/19300) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs772802187). 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 3 affected individuals, 2 were compound heterozygotes that carried a reported pathogenic variant in trans and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Glu609Lys variant is pathogenic (VariationID: 371491; PMID: 32455116, 30228975). In vitro functional studies provide some evidence that the p.Glu609Lys variant may slightly impact protein function (PMID: 30228975). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PM3_strong (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 20, 2024

- -

GBE1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

The GBE1 c.1825G>A variant is predicted to result in the amino acid substitution p.Glu609Lys. This variant was reported in the compound heterozygous state in three unrelated individuals with glycogen storage disease and erythrocyte GBE activity of ~10% (Iijima et al. 2018. PubMed ID: 30228975; Ichimoto et al. 2020. PubMed ID: 32455116). This variant is reported in 0.20% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 21, 2022

- -

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

Jan 22, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 609 of the GBE1 protein (p.Glu609Lys). This variant is present in population databases (rs772802187, gnomAD 0.2%). This missense change has been observed in individual(s) with glycogen storage disease type IV (PMID: 30228975, 32455116). 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: 577677). 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. Experimental studies have shown that this missense change affects GBE1 function (PMID: 30228975). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 08, 2022

Variant summary: GBE1 c.1825G>A (p.Glu609Lys) results in a conservative amino acid change located in the Alpha-amylase/branching enzyme, C-terminal all beta domain (IPR006048) 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 0.00018 in 244706 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.00018 vs 0.0013), allowing no conclusion about variant significance. c.1825G>A has been reported in the literature as a biallelic compound heterozygous genotype in at-least two cases of Glycogen Storage Disease, Type IV with atypical liver pathology and one additional case with milder manifestations diagnosed as non-progressive GSD-IV (example, Inchimoto_2020, Iijima_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Iijima_2018). The most pronounced variant effect results in 53% of normal GBE enzyme activity in-vitro. Authors state that approximately 50% of GBE activity is compatible with the milder forms of GSG IV. Milder manifestations include non-progressive form (NP-GSD IV) and adult polyglucosan body disease (APBD). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Adult polyglucosan body disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.71	P;D
Vest4		0.78
MutPred		0.55		Gain of methylation at E609 (P = 0.0205);.;
MVP		0.88
MPC		0.17
ClinPred		0.39	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs772802187; hg19: chr3-81584455; COSMIC: COSV70102975;