17-80117723-C-T

Variant names:

• chr17-80117723-C-T
• rs61736895
• NM_000152.5:c.2455C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID:33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID:22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815746/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:5
• Conservation: PhyloP100: 2.30
• Publications: 2 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_pathogenic. The variant received 6 ACMG points.

• 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.2455C>T	p.Arg819Trp	missense	Exon 17 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2455C>T	p.Arg819Trp	missense	Exon 18 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2455C>T	p.Arg819Trp	missense	Exon 17 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.2455C>T	p.Arg819Trp	missense	Exon 17 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2455C>T	p.Arg819Trp	missense	Exon 18 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2470C>T	p.Arg824Trp	missense	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000247 AC: 6 AN: 243096 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000391 AC: 57 AN: 1459040 Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 725742

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000898 AC: 4 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111438

Other (OTH) AF: 0.0000332 AC: 2 AN: 60298

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41448

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

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: 10620

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	2	-	Glycogen storage disease, type II (5)
1	1	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		2.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.80		Loss of methylation at R819 (P = 0.0222)
MVP		1.0
MPC		0.54
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.98
Mutation Taster		=22/78	disease causing

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: rs61736895; hg19: chr17-78091522;