rs398123172

Variant names:

• chr17-80113282-G-A
• rs398123172
• NM_000152.5:c.2105G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80113282-G-A
• chr17-80113282-G-C
• chr17-80113282-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PM2_Supporting PM3_Strong PM5 PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2105G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 702 (p.Arg702His). At least 3 unrelated patients were noted to have deficient GAA activity but results were not provided (PMID:26310554, 30897595, 28394184). Two patients are described as having IOPD with clinical symptoms consistent with IOPD reported in one (PMID:26310554). One patient is described as having juvenile-onset Pompe disease with deficient GAA (value not provided) (PMID:18211760). Another patient is reported to have deficient GAA and late-onset Pompe disease (PMID:30897595) (PP4_Moderate). At least one patient is described as having this variant in trans with a variant classified as likely pathogenic by the ClinGen Lysosomal Diseases (LD) VCEP (c.796C>T, p.Pro266Ser; ClinVar Variation ID Variation ID: 556117; SCV002540664.1) (PMID:18211760). At least two patients have been reported with this variant in compound heterozygosity with another variant that has been classified as pathogenic by the ClinGen LD VCEP (c.2297A>C, p.Tyr766Ser, ClinVar Variation ID: Variation ID: 420102, SCV002540647.1, and c.2238G>C, p.Trp746Cys, ClinVar Variation ID: Variation ID: 265160, SCV002032122.1), phase unconfirmed for both (PMID:28394184 and 30897595) (PM3_Strong). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 cells resulted in 5% wild type GAA activity in medium and 13% residual activity in cells with evidence of abnormal synthesizing and processing (PMID:18425781) leading the variant to be described as Class D “potentially mild” indicating that this variant may impact protein function (PS3_supporting). Another missense variant (c.2105G>T, p.Arg702Leu) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP (ClinVar Variation ID: Variation ID: 92472)(PM5). There is a ClinVar entry for this variant (Variation ID: 426278). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_strong, PM5, PP4_moderate, PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815610/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:2
• Conservation: PhyloP100: 9.74
• Publications: 19 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 11 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.
• PM5: 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.2105G>A	p.Arg702His	missense	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2105G>A	p.Arg702His	missense	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2105G>A	p.Arg702His	missense	Exon 15 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.2105G>A	p.Arg702His	missense	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2105G>A	p.Arg702His	missense	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2120G>A	p.Arg707His	missense	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000539 AC: 12 AN: 222484 AF XY: 0.0000582

Gnomad AFR exome AF: 0.0000733

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: 0.0000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000249 AC: 36 AN: 1448060 Hom.: 0 Cov.: 35 AF XY: 0.0000236 AC XY: 17 AN XY: 719012

African (AFR) AF: 0.0000902 AC: 3 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 43050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 38990

South Asian (SAS) AF: 0.0000478 AC: 4 AN: 83600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51940

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5742

European-Non Finnish (NFE) AF: 0.0000217 AC: 24 AN: 1105906

Other (OTH) AF: 0.0000501 AC: 3 AN: 59856

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		9.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.97		Gain of methylation at K697 (P = 0.0379)
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs398123172; hg19: chr17-78087081;