17-80107818-G-A

Variant names:

• chr17-80107818-G-A
• rs121907945
• NM_000152.5:c.877G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PS3_Moderate PM2_Supporting PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.877G>A variant in GAA is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 293 (p.Gly293Arg). Patients with a diagnosis of Pompe disease reported with this variant include five individuals with documented laboratory values showing deficient GAA activity meeting the specifications of the ClinGen LSD VCEP (PMIDs: 23566438, 24590251, 26497565), one of whom also has features reported that are consistent with infantile onset Pompe disease (PMID:31510962) and additional patients reported to be on enzyme replacement therapy but without documentation of residual GAA activity (PMID:18607768, 21605996) (PP4_Moderate). At least 6 patients are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 18607768, 21605996, 23566438, 24590251, 25455803, 29181627, 31710733), c.2481+102_2646+31del (PMID:18429042) and c.716del (p.Leu239fsTer28) (PMID:14695532), and at least two individuals are homozygous for the variant (PMIDs: 31510962, 26497565) (2 x 0.5 points) (PM3_Strong). In addition, two patients are compound heterozygous for the variant and either c.719C>T (p.Phe240Ser; note that reference sequence has a T at position 719) (PMID:25455803) or c.710C>T (p.Ala237Val) (PMIDs: 15668445, 17573812, 17643989. The allelic data from these patients will be used in the classification of p.Phe240Ser and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00006 (2/35062 alleles) in the Latino / Admixed American population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in <2% residual GAA activity in medium and cells (PMIDs 14695532, 19862843). No GAA protein was observed on Western blot of COS cells expressing the variant (PMID 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.931 which is above the threshold of 0.7, evidence that correlates with impact to GAA function, and SpliceAI predicts the creation of a cryptic splice site 2 nucleotides downstream from the variant (PP3). There is a ClinVar entry for this variant (Variation ID: 4036; 2 star review status) with 6 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. )Classification approved by the ClinGen LSD VCEP on Nov. 2, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116622/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 7.93
• Publications: 26 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: Pathogenic. The variant received 10 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.877G>A	p.Gly293Arg	missense	Exon 5 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.877G>A	p.Gly293Arg	missense	Exon 6 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.877G>A	p.Gly293Arg	missense	Exon 5 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.877G>A	p.Gly293Arg	missense	Exon 5 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.877G>A	p.Gly293Arg	missense	Exon 6 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.877G>A	p.Gly293Arg	missense	Exon 5 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000163 AC: 4 AN: 245436 AF XY: 0.0000225

Gnomad AFR exome AF: 0.0000637

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459656 Hom.: 0 Cov.: 56 AF XY: 0.00000689 AC XY: 5 AN XY: 726162

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000449 AC: 2 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111600

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

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

Alfa AF: 0.0000721 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Glycogen storage disease, type II (8)
4	-	-	not provided (4)
1	-	-	Glycogen storage disease due to acid maltase deficiency, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Gain of methylation at G293 (P = 0.0461)
MVP		1.0
MPC		0.59
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.98
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121907945; hg19: chr17-78081617;