rs1555601780

chr17-80113311-CTG-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.2136_2137del(p.Phe713ProfsTer23) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000691 in 1,447,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L712L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 6.08

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 17-80113311-CTG-C is Pathogenic according to our data. Variant chr17-80113311-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 556718.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80113311-CTG-C is described in Lovd as [Pathogenic]. Variant chr17-80113311-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2136_2137del	p.Phe713ProfsTer23	frameshift_variant	15/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2136_2137del	p.Phe713ProfsTer23	frameshift_variant	15/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447030 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 718462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556718). This variant is also known as c.2136-7delGT. This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 25614309). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe713Profs*23) 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). -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Aug 19, 2021	The NM_000152.5:c.2136_2137del (p.Phe713ProfsTer23) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 15/20, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A patient with this variant was reported to have deficient GAA activity and to be on enzyme replacement therapy for Pompe disease (PMID: 25614309, 27896092)(PP4). This patient is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-32-13T>G ( PMID: 25614309, 27896092)(PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 556718; 1 star review status) with one submitter classifying the variant 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 Lysosomal Storage Disorders VCEP (Specification Version 2.0): PVS1, PM2_Supporting, PM3_Supporting, PP4. (Classification approved on August 17th, 2021) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

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: rs1555601780; hg19: chr17-78087110;