rs757458607

chr17-80108554-AC-A

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.1143del(p.Ala382LeufsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,518 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. T381T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 2.92

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 17-80108554-AC-A is Pathogenic according to our data. Variant chr17-80108554-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 370263.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80108554-AC-A is described in Lovd as [Pathogenic]. Variant chr17-80108554-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1143del	p.Ala382LeufsTer10	frameshift_variant	7/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1143del	p.Ala382LeufsTer10	frameshift_variant	7/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248094 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134732

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: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460518 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 726550

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 16, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ala382LeufsTer10 variant in GAA has been reported in 4 Caucasian individuals (including 2 Germans) with Glycogen Storage Disease II (PMID: 24383498, 22676651), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL in ClinVar (Variation ID: 370263). This variant has been identified in 0.0009% (1/111784) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516359). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 382 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. The presence of this variant in combination with a pathogenic variant curated by our study and in 2 individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Ala382LeufsTer10 variant is pathogenic (PMID: 22676651). The phenotype of individuals compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on low GAA activity consistent with disease (PMID: 22676651). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and a few occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2, PP4 (Richards 2015). -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 13, 2023	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Aug 31, 2020	This variant, c.1143del (p.Ala382LeufsTer10), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 0.000008946 in the European non-Finnish population, meeting PM2. At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP's specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting is met based on the specifications on the Clingen LSD VCEP. There is a ClinVar entry for this variant (Variation ID: 370263, 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 30, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370263). This premature translational stop signal has been observed in individual(s) with late-onset Pompe disease (PMID: 22676651, 29122469). This variant is present in population databases (rs757458607, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ala382Leufs*10) 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:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 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: rs757458607; hg19: chr17-78082353;