chr17-80110767-C-T

Variant names:

• chr17-80110767-C-T
• rs148842275
• NM_000152.5:c.1478C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1478C>T variant in GAA is predicted to result in the substitution of proline by leucine at amino acid 493 (p.Pro493Leu). At least 7 probands have been reported with this variant, including one adult and an affected sibling with documented values showing GAA activity below the normal range on dried blood spot assay, and treated with enzyme replacement therapy (ERT) (PMID 24495340), and another four individuals with features consistent with Pompe disease, three of them on enzyme replacement therapy (PMID:25455803, 29181627, 31545528, 33188503). Furthermore, three individuals with the same genotype (thought to be unrelated but cannot be confirmed) were identified in a clinical diagnostic laboratory with GAA activity below the normal range on dried blood spot (PP4_Moderate). Two additional patients have been reported with P493L, but the cDNA change was not provided and, one patient was heterozygous without the identification of a second variant, therefore, this data will not be included (PMID:20033296, 23160972, 31545528), and patient with suspected late onset Pompe disease was identified by newborn screening but was asymptomatic (PMID:33202836). The 7 probands are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. The phase is unconfirmed in all of these patients. The second variant is either c.525delT (PMID:25455803, and 3 presumably unrelated patients identified by a clinical diagnostic laboratory, max 2 patients counted, ClinVar Variation ID: 4033, SCV001443331.1; 2 x 0.5 points), c.1134C>G (p.Tyr378Ter), phase unknown (PMID:29181627, ClinVar Variation ID: 595469, SCV001443283.2, 0.5 points), c.307T>G (p.Cys103Gly) (PMID:24495340, ClinVar Variation ID: 92483, SCV002817442.1, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1, 0.5 points), c.1655T>C (p.Leu552Pro) (PMID:31545528, ClinVar Variation ID: 279811, SCV001371750.2) or c.-32-13T>G (PMID:33188503, ClinVar Variation ID: 4027). 7 x 0.5 points = 3.5 points (PM3_Strong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003 (4/128962 alleles) in the European non-Finnish population, and in gnomAD v4.1. the MAF is 0.00001695 (20/1180038) in the European non-Finnish population. Both are 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 0.911 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, results of functional studies are not available for this variant. There is a ClinVar entry for this variant (Variation ID 379593). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 21, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16608675/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 5.70
• 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: Likely_pathogenic. The variant received 8 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.1478C>T	p.Pro493Leu	missense	Exon 10 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1478C>T	p.Pro493Leu	missense	Exon 11 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1478C>T	p.Pro493Leu	missense	Exon 10 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.1478C>T	p.Pro493Leu	missense	Exon 10 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1478C>T	p.Pro493Leu	missense	Exon 11 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1493C>T	p.Pro498Leu	missense	Exon 10 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152186 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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251208 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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461844 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

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

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	1	-	Glycogen storage disease, type II (6)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.026	D
Polyphen		0.97	D
Vest4		0.94
MVP		1.0
MPC		0.51
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.87
Mutation Taster		=9/91	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: rs148842275; hg19: chr17-78084566;