rs761317813

chr17-80104837-TC-Tchr17-80104837-TC-TCC

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.258del(p.Asn87ThrfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. V84V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: -0.512

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 17-80104837-TC-T is Pathogenic according to our data. Variant chr17-80104837-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551592.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80104837-TC-T is described in Lovd as [Pathogenic]. Variant chr17-80104837-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.258del	p.Asn87ThrfsTer55	frameshift_variant	2/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.258del	p.Asn87ThrfsTer55	frameshift_variant	2/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459918 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726322

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2017	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Aug 19, 2021	The NM_000152.5:c.258del (p.Asn87ThrfsTer55) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). To our knowledge, this variant has not been reported in the literature in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID:551592, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs761317813; hg19: chr17-78078636;