rs543300039

Variant names:

• chr17-80107866-G-A
• rs543300039
• NM_000152.5:c.925G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80107866-G-A
• chr17-80107866-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PM3 PS3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.925G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 309 (p.Gly309Arg). In a cohort of 54 Dutch patients with Pompe disease, the allele frequency of the variant was 5.5%, and evidence suggests that it is a founder variant in that population (PMID 9660056). This variant has been reported in more than 13 individuals diagnosed with Pompe disease; for at least 6 individuals, residual GAA activity is available and is in the deficient range (PMIDs 9660056, 16838077, 23430847, 23601496, 24495340, 27189384), with some patients also reported to be on enzyme replacement therapy and/or to have documentation of symptoms consistent with infantile onset Pompe disease (PMID 23402890, 23430847, 23601496, 24495340) (PP4_Moderate). More data is available in the literature but the maximum strength of evidence for PP4, as specified by the ClinGen LSD VCEP, can already be applied.. Ten of these individuals are compound heterozygous for the variant and a pathogenic variant (PMID:9660056, 16838077, 16917947, 23402890, 23430847), phase unknown in all cases, and one is homozygous (PMID:23601496)(PM3_Very strong). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00005 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In functional studies, when expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.963, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 188797; 2 star review status) with 8 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved on August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA273972/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 7.93
• Publications: 29 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: Pathogenic. The variant received 10 ACMG points.

• PS3: 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.925G>A	p.Gly309Arg	missense	Exon 5 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.925G>A	p.Gly309Arg	missense	Exon 6 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.925G>A	p.Gly309Arg	missense	Exon 5 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.925G>A	p.Gly309Arg	missense	Exon 5 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.925G>A	p.Gly309Arg	missense	Exon 6 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.925G>A	p.Gly309Arg	missense	Exon 5 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000286 AC: 7 AN: 244726 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1459274 Hom.: 0 Cov.: 53 AF XY: 0.0000303 AC XY: 22 AN XY: 725920

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86130

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5382

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111676

Other (OTH) AF: 0.0000166 AC: 1 AN: 60238

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

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: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000567 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
12	-	-	Glycogen storage disease, type II (12)
7	-	-	not provided (7)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.91		Loss of catalytic residue at V310 (P = 0.0242)
MVP		1.0
MPC		0.59
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.99
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs543300039; hg19: chr17-78081665; COSMIC: COSV105124185; COSMIC: COSV105124185;