17-80112622-G-A

Variant names:

• chr17-80112622-G-A
• rs377544304
• NM_000152.5:c.1799G>A

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.1799G>A variant in GAA is a missense variant predicted to result in substitution of arginine by histidine at amino acid 600 (p.Arg600His).This variant has been reported in at least 7 patients including those with symptoms consistent with infantile onset Pompe disease, <10% GAA activity in muscle, and showing improvement on enzyme replacement therapy (PMID:15121988, 24715333); one patient identified on newborn screen with confirmatory GAA activity testing and showing cardiac hypertrophy and arrythmia on cardiac evaluation (PMID:33073007), three patients with features consistent with Pompe disease and GAA activity in the laboratory's affected range in dried blood spots or leukocytes (PMID:2267665, 33741225) (PP4_Moderate). Four patients are compound heterozygous for the variant and another variant in GAA, phase unknown, that has been classified a pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (2 independent probands, PMIDs: 21967859, 2267665), c.2481+110_2646+39del) (2 independent probands, PMID:15121988, 24715333; PMID:2267665), and one homozygote (PMID:33073007) (PM3_Strong). In addition, two patients are compound heterozygous for the variant and another missense change, or c.1465G>A (p.Asp489Asn) (PMID:22711147) or c.1751A>C (p.His584Pro) (PMID:33741225). The allelic data from these patients will be used in the assessment of the other missense change and is not included here to avoid circular logic. The amino acid change was reported in additional patients but the cDNA changes were not provided and so the data is not included (PMID:10338092, 20033296).The highest population minor allele frequency in gnomAD is 0.00003 (1.30606 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).This variant alters the arginine at amino acid 600, a residue that crystallography studies have shown to be important important in the active site architecture and substrate binding of GAA, and therefore has been defined as a critical residue by the ClinGen LSD VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID:29061980) (PM1).This variant results in <2% GAA activity when expressed in COS-7 and HEK 293 cells (PMID:19862843, 24715333), and was shown to be abnormally processed by Western blot analysis, with production of very little of the active 76 kDa form, when expressed in HEK293 cells (PMID:24715333). PS3_Moderate is applied based on two separate studies, one showing GAA deficiency and the other showing abnormal GAA processing (PS3_Moderate).The computational predictor REVEL gives a score of 0.967 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).Three additional missense changes in the same codon have been reported in patients with Pompe disease. The classification of p.Arg600His will be used to to support the classification of the other variants c.1798C>T (p.Arg600Cys) (pathogenic based on classification by the ClinGen LSD VCEP), c.1799G>C (p.Arg600Pro) and c.1799G>T (p.Arg600Leu), and is not used here to avoid circular logic.There is a ClinVar entry for this variant (Variation ID: 370130) with 10 submitters classifying the variant as pathogenic and two as likely pathogenic.In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP crteria applied, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Strong, PM1, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on Oct 18, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815482/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 9.80
• Publications: 21 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.1799G>A	p.Arg600His	missense	Exon 13 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1799G>A	p.Arg600His	missense	Exon 14 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1799G>A	p.Arg600His	missense	Exon 13 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.1799G>A	p.Arg600His	missense	Exon 13 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1799G>A	p.Arg600His	missense	Exon 14 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1814G>A	p.Arg605His	missense	Exon 13 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248322 AF XY: 0.00

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460678 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726680

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52330

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Alfa AF: 0.000489 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Glycogen storage disease, type II (10)
5	-	-	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.2	H
PhyloP100		9.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs377544304; hg19: chr17-78086421; COSMIC: COSV56406566; COSMIC: COSV56406566;