17-80105096-C-T

Variant names:

• chr17-80105096-C-T
• rs564758226
• NM_000152.5:c.510C>T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 1P and 2B. PM2_Supporting BP7 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.510C>T variant in GAA is a synonymous (silent) variant (p.Asp170=) that is not predicted to impact splicing (BP7, BP4). This variant has been detected in at least 14 individuals with Pompe disease (PMIDs 14695532, 30564623, 30922962, 34405923). However, in all but one individual it was found to co-occur with two additional GAA variants. Additionally, studies have shown that c.510C>T frequently occurs in cis with the c.-32-13T>G variant (pathogenic by the ClinGen Lysosomal Disease VCEP) and is associated with an earlier age of onset and lower GAA enzyme activity in fibroblasts compared to individuals with c.-32-13T>G that do not carry c.510C>T (PMIDs 30922962, 34405923). RT-PCR from patients with c.510C>T and c.-32-13T>G and minigene assays demonstrate that c.510C>T modulates the aberrant splicing caused by c.-32-13T>G, but does not have a significant impact on splicing when it occurs in isolation (PMID 30922962). The highest population minor allele frequency in gnomAD v2.1.1. is 0.00008925 (11/123248 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 280956). While it is uncertain if c.510C>T is causative of disease, there is evidence suggesting that this variant acts as a negative modifying factor when it occurs in cis with c.-32-13T>G. Therefore, this variant is classified as a variant of unknown significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): BP4, BP7, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814885/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 B:5
• Conservation: PhyloP100: -3.08
• Publications: 16 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 -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.510C>T	p.Asp170Asp	synonymous	Exon 2 of 20	NP_000143.2
	GAA	NM_001079803.3		c.510C>T	p.Asp170Asp	synonymous	Exon 3 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.510C>T	p.Asp170Asp	synonymous	Exon 2 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.510C>T	p.Asp170Asp	synonymous	Exon 2 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.510C>T	p.Asp170Asp	synonymous	Exon 3 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.510C>T	p.Asp170Asp	synonymous	Exon 2 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000478

GnomAD2 exomes AF: 0.0000536 AC: 13 AN: 242402 AF XY: 0.0000753

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000927

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1459266 Hom.: 0 Cov.: 36 AF XY: 0.0000399 AC XY: 29 AN XY: 725950

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111796

Other (OTH) AF: 0.0000331 AC: 2 AN: 60360

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:3 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

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.510C>T (p.Asp170=) variant in GAA has been reported as a polymorphism in 1 Dutch individual with Glycogen Storage Disease II (PMID: 14695532), and has also been identified in 0.009% (11/123248) of European (non-Finnish) chromosomes chromosomes and 0.006% (2/35320) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs564758226). 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 has been reported as a VUS by EGL Genetic Diagnostics and a likely benign variant by Invitae in ClinVar (Variation ID: 280956). Computational splicing 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: PM2, BP7, BP4 (Richards 2015).

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 19, 2024

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.510C>T variant in GAA is a synonymous (silent) variant (p.Asp170=) that is not predicted to impact splicing (BP7, BP4). This variant has been detected in at least 14 individuals with Pompe disease (PMIDs 14695532, 30564623, 30922962, 34405923). However, in all but one individual it was found to co-occur with two additional GAA variants. Additionally, studies have shown that c.510C>T frequently occurs in cis with the c.-32-13T>G variant (pathogenic by the ClinGen Lysosomal Disease VCEP) and is associated with an earlier age of onset and lower GAA enzyme activity in fibroblasts compared to individuals with c.-32-13T>G that do not carry c.510C>T (PMIDs 30922962, 34405923). RT-PCR from patients with c.510C>T and c.-32-13T>G and minigene assays demonstrate that c.510C>T modulates the aberrant splicing caused by c.-32-13T>G, but does not have a significant impact on splicing when it occurs in isolation (PMID 30922962). The highest population minor allele frequency in gnomAD v2.1.1. is 0.00008925 (11/123248 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 280956). While it is uncertain if c.510C>T is causative of disease, there is evidence suggesting that this variant acts as a negative modifying factor when it occurs in cis with c.-32-13T>G. Therefore, this variant is classified as a variant of unknown significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): BP4, BP7, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024).

not provided Uncertain:2 Benign:2

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAA: BP4, BP7

Jan 22, 2025

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria.

Oct 10, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 29, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

May 07, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.510C>T alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.4e-05 in 242402 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (5.4e-05 vs 0.0042), allowing no conclusion about variant significance. c.510C>T several individuals affected with Juvenile onset Glycogen Storage Disease, Type 2 (Pompe Disease) (Holzwarth_2022, King_2023, Nallamilli_2018), however observed in cis with c.-32-13T>G in almost all cases. Additionally, it lowers ages of onset and lowers GAA enzyme activity in fibroblasts compared to individuals with c.-32-13T>G that do not carry c.510C>T (Bergsma_2019, Nino_2021). At least one experimental study has shown that this variant further reduces the level of normal GAA mRNA in fibroblasts from patients caused by c.-32-13T>G (Bergsma_2019). However, a biochemical study in fibroblasts from an individual compound heterozygous for c.-32-13T>G and c.510C>T shows normal enzyme activity (King_2023), suggesting that this variant alone does not affect GAA activity. The following publications have been ascertained in the context of this evaluation (PMID: 30922962, 14695532, 34852371, 37087815, 30564623, 34405923). ClinVar contains an entry for this variant (Variation ID: 280956). In conclusion, while it is uncertain if this variant is causative of Pompe disease, there is evidence suggesting that this variant acts as a negative modifying factor when it occurs in cis with c.-32-13T>G. Based on the evidence outlined above, the variant was classified as uncertain significance.

Cardiovascular phenotype Benign:1

Sep 24, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.85
DANN	Benign	0.89
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism

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: rs564758226; hg19: chr17-78078895;