rs869320698

Positions:

• chr3-81493812-GCCACCACAC-GACCTGTCATGTAAAAAACA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000158.4(GBE1):​c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GBE1 NM_000158.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.749

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-81493813-CCACCACAC-ACCTGTCATGTAAAAAACA is Pathogenic according to our data. Variant chr3-81493813-CCACCACAC-ACCTGTCATGTAAAAAACA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4	c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT		intron_variant		ENST00000429644.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7	c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT		intron_variant		1	NM_000158.4	P1
GBE1	ENST00000489715.1	c.1930-3358_1930-3350delinsTGTTTTTTACATGACAGGT		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adult polyglucosan body disease Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 27, 2022	The c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant in GBE1 has been reported in 16 individuals with adult polyglucosan body disease (APBD) (PMID: 25665141), but data from large population studies is insufficient to assess the frequency of this variant. Of the 16 affected individuals, all were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant is pathogenic (VariationID: 2777; PMID: 25665141). This variant has also been reported in ClinVar (Variation ID#: 225145) and has been interpreted as likely pathogenic or pathogenic by OMIM, GeneDx, and the Undiagnosed Diseases Network (NIH). In vitro functional studies provide some evidence that the c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant may impact protein function (PMID: 25665141). 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, this variant meets criteria to be classified as pathogenic for autosomal recessive APBD. ACMG/AMP Criteria applied: PS3_moderate, PM3_very-strong, PP3(Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Jul 12, 2021	The variant in the GBE1 gene, c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT, is a deep intronic insertion/deletion. This variant results in a sequence of nine intronic nucleotides being removed and replaced by 20 nucleotides containing an mRNA splice acceptor. It has been found in trans with the c.986A>C variant in 16 patients of Ashkenazi Jewish descent with adult polyglucosan body disease (PMID: 25665141). PCR analysis showed that this variant caused the splicing of exon 15 into an ectopic splice acceptor site, creating an abnormal exon 16 with a new stop codon. The mean GBE activity in compound heterozygotes was 8% of normal compared to 18% of normal in c.986A>C homozygotes, indicating the truncated protein product is unstable (PMID: 25665141). -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 07, 2021	- -

Adult polyglucosan body neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 11, 2016

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2021

In silico analysis supports a deleterious effect on splicing; No data available from control populations to assess the frequency of this variant This variant is associated with the following publications: (PMID: 25665141) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869320698; hg19: chr3-81542964;