rs370246900

Variant names:

• chr3-81536933-T-C
• rs370246900
• NM_000158.4:c.1781A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000158.4(GBE1):​c.1781A>G​(p.Tyr594Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,432,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0240

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16131967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4	c.1781A>G	p.Tyr594Cys	missense_variant	Exon 13 of 16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.1909A>G		non_coding_transcript_exon_variant	Exon 13 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.1781A>G	p.Tyr594Cys	missense_variant	Exon 13 of 16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1	c.1658A>G	p.Tyr553Cys	missense_variant	Exon 13 of 16	2		ENSP00000419638.1
GBE1	ENST00000484687.1	n.182A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000227 AC: 5 AN: 220138 Hom.: 0 AF XY: 0.0000333 AC XY: 4 AN XY: 120284

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: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1432354 Hom.: 0 Cov.: 30 AF XY: 0.0000155 AC XY: 11 AN XY: 711674

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: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000909

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type IV Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine with cysteine at codon 594 of the GBE1 protein (p.Tyr594Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs370246900, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with GBE1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Uncertain	0.68	D;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Benign	0.29
Sift	Benign	0.079	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0060	B;B
Vest4		0.26
MVP		0.78
MPC		0.035
ClinPred		0.15	T
GERP RS		2.5
Varity_R		0.43
gMVP		0.67

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

Other links and lift over

dbSNP: rs370246900; hg19: chr3-81586084;