rs886058900

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000158.4(GBE1):c.1604A>G(p.Tyr535Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,595,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.66

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000158.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 3-81577939-T-C is Pathogenic according to our data. Variant chr3-81577939-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 346787.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4 linkuse as main transcript	c.1604A>G	p.Tyr535Cys	missense_variant	12/16	ENST00000429644.7
GBE1	XR_007095662.1 linkuse as main transcript	n.1732A>G		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GBE1	ENST00000429644.7 linkuse as main transcript	c.1604A>G	p.Tyr535Cys	missense_variant	12/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1 linkuse as main transcript	c.1481A>G	p.Tyr494Cys	missense_variant	12/16	2
GBE1	ENST00000484687.1 linkuse as main transcript	n.5A>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000432

AC:

AN:

231280

Hom.:

AF XY:

0.00000795

AC XY:

AN XY:

125816

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000927

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000485

AC:

AN:

1442918

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

716862

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type IV

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 27, 2022	The p.Tyr535Cys variant in GBE1 has been reported in 2 individuals, in the compound heterozygous state, with GBE1-related disorders (PMID: 20058079, 25728520), segregated with disease in 2 affected relatives from 1 family (PMID: 25728520), and has been identified in 0.002% (3/123296) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs886058900). 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. This variant has also been reported in ClinVar (Variation ID#: 346787) and has been interpreted as likely pathogenic by Illumina Clinical Services Laboratory (Illumina). In vitro functional studies provide some evidence that the p.Tyr535Cys variant may impact protein function (PMID: 25728520). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive GBE1-related disorder. ACMG/AMP Criteria applied: PP3, PP1, PM2, PS3_moderate (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2023	- -

GBE1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The GBE1 c.1604A>G (p.Tyr535Cys) missense variant has been reported in three studies in which it is found in a total of five individuals with either glycogen storage disease type IV or adult polyglucosan body disease, including in four in a compound heterozygous state and in one in a heterozygous state where a second variant was not identified (Massa et al. 2008; Li et al. 2010; Colombo et al. 2015). The variant has also been detected in at least one unaffected heterozygote. The p.Tyr535Cys variant was absent from at least 200 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Tyr535 residue is noted to be conserved. Functional studies in individual cells demonstrate that the variant results in enzyme activity in liver with some residual activity (30%) seen in cultured fibroblasts (Li et al. 2010). Based on the evidence the p.Tyr535Cys variant is classified as likely pathogenic for GBE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 535 of the GBE1 protein (p.Tyr535Cys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with glycogen storage disease type IV (PMID: 20058079, 25728520). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 346787). 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 expected to disrupt GBE1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.86

Gain of catalytic residue at L536 (P = 0.0915);.;

MVP

0.98

MPC

0.26

ClinPred

1.0

GERP RS

5.8

Varity_R

0.94

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over