17-80112015-A-T

Variant names:

• chr17-80112015-A-T
• rs747150965
• NM_000152.5:c.1669A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PS3_Moderate PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1669A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 557 (p.Ile557Phe). Three probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant (PMIDs 23884227, 25612604, clinical laboratory data), two with documented deficiency of GAA activity (PMIDs 23884227, 25612604) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.1978C>T (p.Arg660Cys) (clinical laboratory data); the variants are confirmed in trans by parental testing. The other two patients are compound heterozygous for the variant and a variant classified as uncertain significance by the ClinGen LSD VCEP, either c.2132C>G (p.Thr711Arg) or c.1385T>C (p.Leu462Pro). The allelic data for these latter two patients will be used in the assessment of p.Thr711Arg or p.Leu462Pro and is not included here to avoid circular logic (PM3). Two additional patients have been reported who were identified by newborn screening and carry pseudodeficiency variants; one asymptomatic and compound heterozygous for the variant and p.Thr711Arg (PMID:20080426), and the other heterozygous for the variant and presumably unaffected (PMID 31076647). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 2.7% GAA activity in cells and 0.3% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.662 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants, c.1669A>G (p.Ile557Val) (ClinVar Variation ID: 856959) and c.1670T>G (p.Ile557Ser) (PMID:26474166), in the same codon have been reported in patients with Pompe disease. However, these variants have been classified as variants of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 558634; 1 star review status) with one submitter classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401368911/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 1.28
• Publications: 11 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 7 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.
• 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.1669A>T	p.Ile557Phe	missense	Exon 12 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1669A>T	p.Ile557Phe	missense	Exon 13 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1669A>T	p.Ile557Phe	missense	Exon 12 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.1669A>T	p.Ile557Phe	missense	Exon 12 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1669A>T	p.Ile557Phe	missense	Exon 13 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1684A>T	p.Ile562Phe	missense	Exon 12 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.66
Sift	Benign	0.043	D
Sift4G	Uncertain	0.059	T
Polyphen		0.069	B
Vest4		0.81
MutPred		0.82		Loss of sheet (P = 0.1158)
MVP		0.98
MPC		0.24
ClinPred		0.93	D
GERP RS		2.4
Varity_R		0.36
gMVP		0.87
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs747150965; hg19: chr17-78085814;