rs1555602692

chr17-80117076-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000152.5(GAA):c.2300del(p.Phe767SerfsTer14) variant causes a frameshift 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 1.94

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80117076-CT-C is Pathogenic according to our data. Variant chr17-80117076-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 555341.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80117076-CT-C is described in Lovd as [Pathogenic]. Variant chr17-80117076-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2300del	p.Phe767SerfsTer14	frameshift_variant	16/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2300del	p.Phe767SerfsTer14	frameshift_variant	16/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 01, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Aug 27, 2021	The NM_000152.5:c.2300del (p.Phe767SerfsTer14) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Western blot of protein from the cultured skin fibroblasts of a patient with this variant showed no GAA cross-reactive material i.e. CRIM-negative (PMID: 22252923), supporting that c.2300del is a loss of function variant (PVS1). This patient has <1% normal GAA activity in skin fibroblasts (PP4_Moderate) and is homozygous for the variant (PMID: 22252923, personal communication) (PM3_Supporting). A patient with Pompe disease who is heterozygous for the variant has been reported but further details are unavailable and the second variant was not reported (PMID: 18425781). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555341; 1 star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 17, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 555341). This premature translational stop signal has been observed in individual(s) with GAA-related conditions (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe767Serfs*14) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs1555602692; hg19: chr17-78090875;