rs763359208

chr17-80119283-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000152.5(GAA):c.2815_2816del(p.Val939LeufsTer78) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 0.766

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.508 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80119283-CTG-C is Pathogenic according to our data. Variant chr17-80119283-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371481.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80119283-CTG-C is described in Lovd as [Pathogenic]. Variant chr17-80119283-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2815_2816del	p.Val939LeufsTer78	frameshift_variant	20/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2815_2816del	p.Val939LeufsTer78	frameshift_variant	20/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251298 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461778 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change results in a frameshift in the GAA gene (p.Val939Leufs*78). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the GAA protein and extend the protein by 63 additional amino acid residues. This variant is present in population databases (rs763359208, gnomAD 0.02%). This frameshift has been observed in individuals with Pompe disease (PMID: 21757382, 24269976, 28394184, 29122469). ClinVar contains an entry for this variant (Variation ID: 371481). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2022	Variant summary: GAA c.2815_2816delGT (p.Val939LeufsX78) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 1.2e-05 in 251298 control chromosomes. c.2815_2816delGT has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic n=2, likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 19, 2021	The NM_000152.5: c.2815_2816del (p.Val939LeufsTer78) variant in GAA is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. The frameshift begins at amino acid 939; the normal GAA gene product is 952 amino acids in length. Hence <10% of the normal product is missing. The impact of adding an abnormal sequence of 78 amino acids to the C terminus of GAA, due to the frameshift, is unknown (PVS1_Moderate). At least 8 patients with this variant who have been diagnosed with Pompe disease have been described including 2 patients for whom residual GAA activity was provided and was either <1% normal in cultured skin fibroblasts (PMID 22538254) or below the normal range in dried blood spots (https://doi.org/10.3390/metabo11070446). One of these patients and at least 2 additional patients were on enzyme replacement therapy (PMID 22538254, 25316892, 32373469, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf) (PP4_Moderate). The reported patients include compound heterozygotes for the variant and another pathogenic/likely pathogenic variant in GAA including for c.118C>T (p.Arg40Ter) (PMID 24269976, ClinVar SCV SCV001371737.1), c.1935C>A (p.Asp645Glu) (PMIDs 32373469, 28394184, 22538254), c.2238G>C (p.Trp746Cys) (PMID 25316892, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf,), and c.2585delG (PMID 28394184)(PM3_Strong). Another patient has been reported as compound heterozygous for the variant and c.266G>T (p.Arg89Leu) (https://doi.org/10.3390/metabo11070446). The in trans data from this patient will be used for the assessment of p.Arg89Leu and is not included here in order to avoid circular logic. For another patient described with Pompe disease and the variant, the second GAA variant was not identified (PMID 10338092). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001631 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371481, 2 star review status) with 2 submitters classifying the variant as pathogenic and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PM3_Strong, PVS1_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen LSD VCEP - Oct.19.2021) -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 04, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Val939LeufsTer78 variant in GAA has been reported in 2 Malaysian individuals with Glycogen Storage Disease II (Wahab, Yakob, and Jalil, 2013), and has also been reported pathogenic by Counsyl in ClinVar (Variation ID: 371481). This variant has been identified in 0.0174% (3/17242) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057517308). 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 939 and leads to a premature termination codon 78 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2022	- -

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: rs763359208; hg19: chr17-78093082;