rs28937909

Variant names:

• chr17-80112914-G-A
• rs28937909
• NM_000152.5:c.1927G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80112914-G-A
• chr17-80112914-G-T

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PS3_Moderate PM2_Supporting PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1927G>A variant in GAA is predicted to result in the substitution of glycine by arginine at amino acid 643 (p.Gly643Arg). Numerous individuals have been reported with this variant and specific features of Pompe disease including GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay; patients with specific features of infantile onset Pompe disease (including cardiac features and hypotonia_, and on enzyme replacement therapy (PMIDs: 8401535, 17723315, 23430912, 23609349 24158270, 25783438, 26349193, 26497565) (PP4_Moderate). The variant has been reported in patients with Pompe disease who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP. In these cases, the second variant includes c.-32-13T>G (ClinVar Variation ID: 4027) (at least 10 cases; maximum 2 x 0.5 points; PMID:16917947, 18607768, 20308911, 23609349, 24158270, 25396301, 25783438, 27862019, 30155607), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1 (2 cases, 2 x 0.5 points) (PMID:18429042, 23430912), c.1064T>C (p.Leu355Pro) (ClinVar Variation ID: 284093, SCV001371747.2) (0.5 points, PMID:18429042), c.236_246del (p.Pro79fsTer) (ClinVar Variation ID: 371302, SCV001443298.1 (0.5 points, PMID:19588081), and c.2662G>T (p.Glu888Ter) (ClinVar Variation ID: 578595, SCV001371767.1 (0.5 points, PMID:28394184). First cousins have been reported who are compound heterozygous for the variant (inherited from their heterozygous mothers who are sisters) and another pathogenic variant in GAA variant; c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) in one individual, and "deletion of exon 18" in the other individual (PMID:26349193). In each case, the second variant was shown to be inherited from the father. Although the genotypes are different, only one case will be counted from this family, as they are related (1 point, pathogenic variant confirmed in trans). At least 2 cases are homozygous for the variant (max 2 x 0.5 points, PMID:18429042, 24002816, 26497565, 30023291). Additional cases are compound heterozygous for the variant and either c.2040G>A (PMID:17723315) or c.2173C>T (p.Arg725Trp) (PMID:8401535). The in trans data for these patients was used in the classification of the other variant as is not included here to avoid circular logic. Finally, the variant is reported in other cases and publications without sufficient evidence to apply PM3 (PMID:9521422, 17915575, 19862843, 22081099, 29880332) Additional cases may be available in the literature but PM3 is already applied at very strong (>5 points) (PM3_VeryStrong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003667 (4/109080 alleles) in the European non-Finnish population. In gnomAD v4.1, the MAF is 0.00003224 (40/1178798 alleles) in the European non-Finnish population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The activity of this variant, when expressed in COS cells, has been analyzed in several studies (PMIDs: 8401535, 9521422, 19862843) and varies from <2%-6% with 4MUG and ~3% wild type activity in cells with glycogen. Pulse chase analysis showed that the protein is abnormally processed, with most of the protein remaining as precursor (PMID:8401535) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 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: 4023). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116596/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 9.82
• Publications: 32 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

Our verdict: Pathogenic. The variant received 8 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.1927G>A	p.Gly643Arg	missense	Exon 14 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1927G>A	p.Gly643Arg	missense	Exon 15 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1927G>A	p.Gly643Arg	missense	Exon 14 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.1927G>A	p.Gly643Arg	missense	Exon 14 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1927G>A	p.Gly643Arg	missense	Exon 15 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1942G>A	p.Gly648Arg	missense	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000248 AC: 6 AN: 242074 AF XY: 0.0000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1458226 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22 AN XY: 725064

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000225 AC: 1 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1110790

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 33

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Glycogen storage disease, type II (11)
3	-	-	not provided (3)
1	-	-	Glycogen storage disease due to acid maltase deficiency, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		9.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Loss of catalytic residue at V642 (P = 0.0605)
MVP		0.97
MPC		0.59
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: 2

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

Other links and lift over

dbSNP: rs28937909; hg19: chr17-78086713;