chr17-80110945-T-C

Variant names:

• chr17-80110945-T-C
• rs786204720
• NM_000152.5:c.1556T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PS3_Moderate PM2_Supporting PM3_Strong PM1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1556T>C variant in GAA is a missense variant predicted to cause substitution of methionine by threonine at amino acid 519 (p.Met519Thr). This variant has been detected in at least 4 individuals with Pompe disease. Of those individuals, 3 were compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LD VCEP, phase unconfirmed, either c.525del (ClinVar Variation ID: 4033, SCV001443331.1) (PMID:14695532), c.1441T>C (p.Trp481Arg) (ClinVar Variation ID: 189007, SCV004227917.1) (PMID:31086307), or c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu] (ClinVar Variation ID 325781/325782) (Clinical laboratory data); One individual was homozygous for the variant (PMID:33741225) (PM3_Strong). At least 1 patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in dried blood spot (PMID:33741225) and 2 patients were reported to have symptoms consistent with infantile onset Pompe disease (PMID:14695532) (PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30616 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.983 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 resulted in <2% wild type GAA activity with western blot data showing decreased level of mature protein, indicating that this variant may impact protein function (PMIDs: 19862843, 14695532) (PS3_Moderate). This variant alters amino acid M519, a residue that crystallography studies have shown to be important in the active site of GAA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID:29061980) (PM1). There is a ClinVar entry for this variant (Variation ID: 189124). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_strong, PP4_moderate, PM1, PS3_moderate, PP3, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274402/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:1
• Conservation: PhyloP100: 6.02
• 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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.1556T>C	p.Met519Thr	missense	Exon 11 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1556T>C	p.Met519Thr	missense	Exon 12 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1556T>C	p.Met519Thr	missense	Exon 11 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.1556T>C	p.Met519Thr	missense	Exon 11 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1556T>C	p.Met519Thr	missense	Exon 12 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1571T>C	p.Met524Thr	missense	Exon 11 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251282 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461648 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727110

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

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Glycogen storage disease, type II (9)
2	1	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of glycosylation at M519 (P = 0.025)
MVP		1.0
MPC		0.58
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs786204720; hg19: chr17-78084744;