rs767882689

Positions:

• chr17-80105110-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP4 PM3_Supporting

This summary comes from the ClinGen Evidence Repository: This variant, c.525_526del (p.Asn177ProfsTer11), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of this variant in an individual with no GAA cross-reactive immunological material in cultured skin fibroblasts (PMID 22252923, 23825616, 31342611). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003288 in the South Asian population, meeting PM2. One individual with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied. There is a ClinVar entry for this variant (Variation ID: 189057, 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 applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274328/MONDO:0009290/010

• 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: 1.31

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 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.525_526del	p.Asn177ProfsTer11	frameshift_variant	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.525_526del	p.Asn177ProfsTer11	frameshift_variant	2/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239740 Hom.: 0 AF XY: 0.00000760 AC XY: 1 AN XY: 131658

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: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456768 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 724508

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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 11, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 06, 2023	ClinVar contains an entry for this variant (Variation ID: 189057). This sequence change creates a premature translational stop signal (p.Asn177Profs*11) 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). This variant is present in population databases (rs767882689, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 22252923). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 23, 2020	The p.Asn177ProfsTer11 variant in GAA has been reported in 6 individuals (including 2 Middle Eastern and 1 Asian individual) with Glycogen Storage Disease II (PMID: 22252923, 23825616, 25455803; DOI: 10.1016/j.ymgme.2017.12.198), and has also been reported in ClinVar (Variation ID: 189057). This variant has been identified in 0.0033% (1/30410) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs767882689). 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 177 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. This variant is noted as homozygous in two individuals with Glycogen Storage Disease II (PMID: 23825616, 25455803). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 02, 2020	This variant, c.525_526del (p.Asn177ProfsTer11), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of this variant in an individual with no GAA cross-reactive immunological material in cultured skin fibroblasts (PMID 22252923, 23825616, 31342611). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003288 in the South Asian population, meeting PM2. One individual with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied. There is a ClinVar entry for this variant (Variation ID: 189057, 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 applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs767882689; hg19: chr17-78078909;