17-80110020-A-T

Variant names:

• chr17-80110020-A-T
• rs886043148
• NM_000152.5:c.1402A>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.1402A>T variant in GAA is a missense variant predicted tocause substitution of isoleucine by phenylalanine at amino acid 468 (p.Ile468Phe). This variant has been identified in at least four unrelated individuals described as having Pompe disease, including two patients with LOPD receiving ERT (PMID:37701327, 25037089). One of these patients has documented deficiency of GAA in DBS. One individual is part of a cohort of patients with LOPD receiving ERT, although GAA enzyme is not reported (PMID:37701327). This meets criteria for PP4_moderate. This variant has been reported in compound heterozygosity (phase unknown) in three unrelated patients with the common splice site variant c.-32-13T>G, meeting criteria for PM3. It has also been reported in one individual with confirmed deficient GAA in DBS, muscle, and skin fibroblast with no second variant reported on sequencing or deletion/duplication analysis (PMID:25037089). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00002 (1/59986 alleles) in the Admixed American population, which is 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 0.747, which meets the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 269826), 1-star review status) with 9 submitters classifying the variant as likely pathogenic (1) and uncertain significance (8). In summary, this 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 Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10605170/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:7
• Conservation: PhyloP100: 4.80
• Publications: 8 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 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.1402A>T	p.Ile468Phe	missense	Exon 9 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1402A>T	p.Ile468Phe	missense	Exon 10 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1402A>T	p.Ile468Phe	missense	Exon 9 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.1402A>T	p.Ile468Phe	missense	Exon 9 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1402A>T	p.Ile468Phe	missense	Exon 10 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1402A>T	p.Ile468Phe	missense	Exon 9 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 34

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460956 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726804

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52670

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	5	-	Glycogen storage disease, type II (8)
1	2	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	D
Vest4		0.93
MutPred		0.77		Gain of sheet (P = 0.0827)
MVP		1.0
MPC		0.67
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.94
Mutation Taster		=38/62	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: rs886043148; hg19: chr17-78083819;