17-80108537-G-T

Variant names:

• chr17-80108537-G-T
• rs142752477
• NM_000152.5:c.1124G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PM2_Supporting PM3_Strong PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1124G>T (p. Arg375Leu) variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 375. This variant has been detected in at least 4 individuals with Pompe disease. Of those, at least 2 patients with late onset Pompe disease from Italy are documented, with reduced GAA activity in leukocytes or muscle. These patients are compound heterozygous, phase unknown, for c.1124G>T (p.Arg375Leu) and the pathogenic variant c.-32-13T>G i(PMIDs: 24158270, 22081099). One proband with severe infantile Pompe was reported to be compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed in trans, and another patient with infantile-onset Pompe disease was homozygous for the variant (PM3_Strong; PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001787 (2/111942 alleles) in the European (non-Finnish) population, which is lower than threshold for PM2_Supporting (<0.001), meeting PM2_Supporting. Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity (PMID:18429042) (PS3_supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7 (PP3). Another missense variant [c.1124G>A (p.Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID:21757382, 21484825) . However this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is ClinVar entry for the variant (Variation ID: 283230, two star review status) with six submitters classifying the variant as Pathogenic/Likely Pathogenic. In summary, c.1124G>T (p.Arg375Leu) variant meets the criteria to be classified as likely pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PM3_strong ; PP4_Moderate; PS3_supporting; PM2_Supporting, PP3. (Classification approved by the ClinGen LSD VCEP on December 6, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815178/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 7.56
• Publications: 27 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: Likely_pathogenic. The variant received 9 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.1124G>T	p.Arg375Leu	missense	Exon 7 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1124G>T	p.Arg375Leu	missense	Exon 8 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1124G>T	p.Arg375Leu	missense	Exon 7 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.1124G>T	p.Arg375Leu	missense	Exon 7 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1124G>T	p.Arg375Leu	missense	Exon 8 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1124G>T	p.Arg375Leu	missense	Exon 7 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248456 AF XY: 0.0000148

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: 0.00000205 AC: 3 AN: 1460556 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 726574

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52410

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Glycogen storage disease, type II (8)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.95		Loss of MoRF binding (P = 0.0472)
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.96
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: rs142752477; hg19: chr17-78082336;