rs747610090

Variant names:

• chr17-80108818-T-A
• rs747610090
• NM_000152.5:c.1316T>A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1316T>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 439 (p.Met439Lys). At least 14 patients have been reported with this variant and features consistent with Pompe disease. This includes 7 patients with documented laboratory values showing deficiency of GAA activity, below the reference range for normal activity in leukocytes (PMIDs: 17092519, 21940687, 23884227, 25388776, 28433475, 30360039), some of whom are also reported to have histological features of Pompe disease in muscle (PMID:20202878, 30894207), and/or documented features of infantile onset Pompe disease including muscle weakness and cardiomyoapthy (PMID:33344388) and/or on enzyme replacement therapy (PMID:30894207, 31193175) (PP4_Moderate). Note that pseudodeficiency variants, (p.Gly576Ser and p.Glu689Lys) were confirmed to be absent in at least one of these cases (PMID 28433475). Of these patients, 7 are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.1798C>T (p.Arg600Cys) (PMID:20202878; phase unknown, 0.5 points), c.2238G>C (p.Trp746Cys) (PMID:30894207, confirmed in trans, 1 point) (PMID:25388776, unknown phase, 0.5 points), c.546G>T (PMID:28433475, unknown phase, 0.5 points), c.2407_2413del (p.Gln803Ter) (PMID:23884227, unknown phase, 0.5 points), and c.1579_1580del (p.Arg527GlyfsTer3) (PMID:30360039, phase unknown, 0.5 points), and c.1225dup (PMID:29869463; phase unknown, 0.25 points); and one patient is homozygous (PMID:29124014) (0.5 points). Total 4.25 points (PM3_VeryStrong). Additional patients have been reported who are compound heterozygous for the variant and c.796C>T (p.Pro266Ser) (PMID:17092519, 29044175, 31850350), c.1225dup (PMID:29869463), and c.1309C>T (p.Arg437Cys) (PMID:25388776) but the allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. Additional data was not included due to uncertainty about the nomenclature of the second variant (PMIDs: 20202878, 21940687). The highest population minor allele frequency in gnomAD is 0.00038 (6/15644 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells the variant has <2% normal activity and does not show mature GAA protein on western blot (PMID 19862843) (PM3_Moderate). The computational predictor REVEL gives a score of 0.784 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: 371305, 2 star review status) with 3 submitters classifying the variant as pathogenic and 4 as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications version 2): PM3_VeryStrong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815258/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 7.49
• Publications: 26 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.1316T>A	p.Met439Lys	missense	Exon 8 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1316T>A	p.Met439Lys	missense	Exon 9 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1316T>A	p.Met439Lys	missense	Exon 8 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.1316T>A	p.Met439Lys	missense	Exon 8 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1316T>A	p.Met439Lys	missense	Exon 9 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1316T>A	p.Met439Lys	missense	Exon 8 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000284 AC: 6 AN: 210934 AF XY: 0.0000348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000384

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000624 AC: 9 AN: 1441610 Hom.: 0 Cov.: 36 AF XY: 0.00000699 AC XY: 5 AN XY: 715714

African (AFR) AF: 0.00 AC: 0 AN: 33086

American (AMR) AF: 0.00 AC: 0 AN: 41860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25736

East Asian (EAS) AF: 0.000233 AC: 9 AN: 38628

South Asian (SAS) AF: 0.00 AC: 0 AN: 83830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102618

Other (OTH) AF: 0.00 AC: 0 AN: 59516

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Glycogen storage disease, type II (8)
1	-	-	Glycogen storage disease (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	0.0083
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.096	B
Vest4		0.91
MutPred		0.91		Loss of stability (P = 0.0308)
MVP		0.99
MPC		0.20
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.95
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs747610090; hg19: chr17-78082617; COSMIC: COSV100163128; COSMIC: COSV100163128;