rs7215458

Variant names:

• chr17-80109970-C-G
• rs7215458
• NM_000152.5:c.1352C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1352C>G variant in GAA is a missense variant predicted to result in the substitution of proline by arginine at amino acid 451 (p.Pro451Arg).The highest population minor allele frequency in gnomAD v4.1.0 is 0.004835 (363/75080) alleles, including 4 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up). The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID:29149851). The variant was also reported in a patient with autism spectrum disorder but no reported diagnosis of Pompe disease (PMID:37492102). The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281330). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert panel on May 20, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815294/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 3.66
• Publications: 6 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1352C>G	p.Pro451Arg	missense	Exon 9 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1352C>G	p.Pro451Arg	missense	Exon 10 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1352C>G	p.Pro451Arg	missense	Exon 9 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1352C>G	p.Pro451Arg	missense	Exon 9 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1352C>G	p.Pro451Arg	missense	Exon 10 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1352C>G	p.Pro451Arg	missense	Exon 9 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152278 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000380 AC: 95 AN: 250328 AF XY: 0.000214

Gnomad AFR exome AF: 0.00441

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1460998 Hom.: 2 Cov.: 32 AF XY: 0.000179 AC XY: 130 AN XY: 726806

African (AFR) AF: 0.00523 AC: 175 AN: 33476

American (AMR) AF: 0.000380 AC: 17 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86248

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52690

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111906

Other (OTH) AF: 0.000613 AC: 37 AN: 60368

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152396 Hom.: 2 Cov.: 34 AF XY: 0.00111 AC XY: 83 AN XY: 74520

African (AFR) AF: 0.00452 AC: 188 AN: 41604

American (AMR) AF: 0.000327 AC: 5 AN: 15312

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: 4830

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

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68042

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

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.00154

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000437 AC: 53

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type II (5)
-	-	2	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	-	1	GAA-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.45
Sift	Benign	0.070	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.96	D
Vest4		0.52
MVP		1.0
MPC		0.49
ClinPred		0.042	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.74
Mutation Taster		=99/1	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: rs7215458; hg19: chr17-78083769;