rs786204727

Variant names:

• chr17-80112648-T-TA
• rs786204727
• NM_000152.5:c.1826dupA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PM3 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross-reactive immunological material in cultured fibroblasts from a patient with the variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 in the European non-Finnish population, meeting PM2. Two individuals meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported who are compound heterozygous for the variant and a unique pathogenic variant; one of these patients is compound heterozygous for the variant and c.525delT, and the other patient is compound heterozygous for the variant and c.2238G>A (p.Trp746Ter) (PMIDs 12897283, 25741864). Therefore, PP4 and PM3 can be applied. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274414/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift, stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 2.23
• Publications: 15 publications found

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]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 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 rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1826dupA	p.Tyr609fs	frameshift_variant, stop_gained	Exon 13 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1826dupA	p.Tyr609fs	frameshift_variant, stop_gained	Exon 13 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000816 AC: 2 AN: 245124 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460378 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726522

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Jan 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Tyr609Ter variant in GAA has been reported in at least 4 individuals (including at least 1 Dutch individual) with Glycogen Storage Disease II (PMID: 14695532, 12897283, 25741864, 22252923), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics in ClinVar (Variation ID: 189144). This variant has been identified in 0.00002% (2/110126) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778892297). 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 leads to a premature termination codon at position 609, which is 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. The presence of this variant in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr609Ter variant is pathogenic (PMID: 25741864, 12897283). Another pathogenic variant, c.1827delC (p.Tyr609Ter), has been reported with the same position and amino acid change (PMID: 14695532, 26693141). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on multiple reports of this variant in CRIM-negative cohorts and abnormally low GAA activity detected in the fibroblasts of one individual heterozygous for this variant (PMID: 22252923, 25741864, 12897283). 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 multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015). -

Feb 14, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross-reactive immunological material in cultured fibroblasts from a patient with the variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 in the European non-Finnish population, meeting PM2. Two individuals meeting the ClinGen LSD VCEP's specifications for PP4 have been reported who are compound heterozygous for the variant and a unique pathogenic variant; one of these patients is compound heterozygous for the variant and c.525delT, and the other patient is compound heterozygous for the variant and c.2238G>A (p.Trp746Ter) (PMIDs 12897283, 25741864). Therefore, PP4 and PM3 can be applied. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. -

Jan 22, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr609*) 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 (rs754952153, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 12897283, 24269976, 25846667, 29124014). ClinVar contains an entry for this variant (Variation ID: 189144). For these reasons, this variant has been classified as Pathogenic. -

Apr 13, 2025

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jul 25, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via a mouse model homozygous knock-in for the p.(Y609X) variant that has features of Infantile-onset Pompe Disease (IOPD) (Huang et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31254424, 33301762, 12897283, 25846667, 29124014, 32587263) -

Aug 20, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204727; hg19: chr17-78086447;