rs148578399

Variant names:

• chr17-80107590-G-A
• rs148578399
• NM_000152.5:c.726G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80107590-G-A
• chr17-80107590-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.726G>A variant in GAA is a synonymous (silent) variant (p.Ala242=) that is predicted to impact splicing. This variant has been detected in at least 10 individuals with low GAA activity. Of those individuals, 8 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.726G>A/c.525delT; 5 patients with the genotype c.−32-13T>G; 726G>A, confirmed in trans in 3 patients, PMID:36310651; c.726G>A / c.671G>A; c.726G>A / c.1979G>A; c.726G>A and c.2560C>T), however there is no diagnosis of Pompe disease and PM3 and PP4 are not met. The computational splicing predictor SpliceAI gives a score of 0.96 for acceptor gain, predicting that the variant creates a new cryptic splice site that is stronger than the original splice site. VarSeak also classifies this variant as having a likely splicing effect by generating a cryptic splice site 35 nucleotides downstream of the authentic splice site with a higher score, meeting PP3. This is confirmed by RNA sequencing data for an individual with the c.726G>A variant demonstrated that the variant impacts splicing by introducing an alternate splice site that results in exon shrinkage. The data suggest that this results in a frameshift and introduces a premature termination codon, however the expression is not reduced, indicating a truncated protein is produced (PMID:35304488), meeting PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 285366, 1 star review status) with 10 submitters classifying the variant as VUS (4 submitters), likely benign (3 submitters), and benign (1 submitter). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PP3, PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on Sept. 19, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815004/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 B:6
• Conservation: PhyloP100: -4.12
• Publications: 10 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: Uncertain_significance. The variant received 2 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.726G>A	p.Ala242Ala	synonymous_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.726G>A	p.Ala242Ala	synonymous_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152090 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 251126 AF XY: 0.000147

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1460916 Hom.: 0 Cov.: 33 AF XY: 0.0000853 AC XY: 62 AN XY: 726784

African (AFR) AF: 0.00254 AC: 85 AN: 33474

American (AMR) AF: 0.000537 AC: 24 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52618

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111898

Other (OTH) AF: 0.000265 AC: 16 AN: 60368

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152208 Hom.: 0 Cov.: 34 AF XY: 0.000820 AC XY: 61 AN XY: 74404

African (AFR) AF: 0.00301 AC: 125 AN: 41524

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67986

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000750 Hom.: 0

Bravo AF: 0.00100

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:2 Benign:5

Sep 19, 2023

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.726G>A variant in GAA is a synonymous (silent) variant (p.Ala242=) that is predicted to impact splicing. This variant has been detected in at least 10 individuals with low GAA activity. Of those individuals, 8 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.726G>A/c.525delT; 5 patients with the genotype c.−32-13T>G; 726G>A, confirmed in trans in 3 patients, PMID: 36310651; c.726G>A / c.671G>A; c.726G>A / c.1979G>A; c.726G>A and c.2560C>T), however there is no diagnosis of Pompe disease and PM3 and PP4 are not met. The computational splicing predictor SpliceAI gives a score of 0.96 for acceptor gain, predicting that the variant creates a new cryptic splice site that is stronger than the original splice site. VarSeak also classifies this variant as having a likely splicing effect by generating a cryptic splice site 35 nucleotides downstream of the authentic splice site with a higher score, meeting PP3. This is confirmed by RNA sequencing data for an individual with the c.726G>A variant demonstrated that the variant impacts splicing by introducing an alternate splice site that results in exon shrinkage. The data suggest that this results in a frameshift and introduces a premature termination codon, however the expression is not reduced, indicating a truncated protein is produced (PMID: 35304488), meeting PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 285366, 1 star review status) with 10 submitters classifying the variant as VUS (4 submitters), likely benign (3 submitters), and benign (1 submitter). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PP3, PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on Sept. 19, 2023) -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely benign

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

The c.726G>A (p.Ala242=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL and Illumina), a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories), and a benign variant (by Invitae) in ClinVar (Variation ID: 285366). This variant has been identified in 0.2769% (69/24916) of African chromosomes, including 1 homozygote, and 0.04516% (16/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148578399). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015). -

Oct 24, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:3 Benign:1

Jan 18, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33073003, 33073007, 33202836, 36310651) -

Jan 17, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.726G>A variant (also known as p.A242A), located in coding exon 3 of the GAA gene, results from a G to A substitution at nucleotide position 726. This nucleotide substitution does not change the alanine at codon 242. This alteration has been reported in newborn screening programs for Pompe disease (Tang H et al. Int J Neonatal Screen, 2020 Mar;6:9; Ficicioglu C et al. Int J Neonatal Screen, 2020 Nov;6; Gragnaniello V et al. Mol Genet Metab Rep, 2022 Dec;33:100929; Burton BK et al. Int J Neonatal Screen, 2020 Mar;6:4). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	20
DANN	Benign	0.67
PhyloP100		-4.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148578399; hg19: chr17-78081389;