rs1555602703

Variant names:

• chr17-80117092-T-C
• rs1555602703
• NM_000152.5:c.2314T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PP4 PS3_Moderate PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2314T>C variant in GAA is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 772 (p.Trp772Arg). This variant has been detected in at least 1 individual with Pompe disease that was compound heterozygous for the variant and a pathogenic variant (PMID:31619483, 18757064) (PM3_Supporting). At least 1 patient with this variant had documented GAA deficiency in leukocytes or fibroblasts was noted to have deficient GAA activity but results were not provided and was reported to be eligible for enzyme replacement therapy for Pompe disease (PMID:31619483, 18757064) (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 5% wild type GAA activity and evidence of abnormal GAA synthesis and processing leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID:18425781) (PS3_Moderate). The computational predictor REVEL gives a score of 0.93 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: 552527; 1 star review status) with 1 submitter classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PS3_Moderate, PM2_Supporting, PP3, PP4, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401324918/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 7.51
• Publications: 0 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2314T>C	p.Trp772Arg	missense	Exon 16 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2314T>C	p.Trp772Arg	missense	Exon 17 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2314T>C	p.Trp772Arg	missense	Exon 16 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2314T>C	p.Trp772Arg	missense	Exon 16 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2314T>C	p.Trp772Arg	missense	Exon 17 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.2314T>C	p.Trp772Arg	missense	Exon 16 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Glycogen storage disease, type II (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		7.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-14	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.97		Gain of catalytic residue at W772 (P = 0.0553)
MVP		1.0
MPC		0.73
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555602703; hg19: chr17-78090891;