rs200586324

Variant names:

• chr17-80104852-G-A
• rs200586324
• NM_000152.5:c.266G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80104852-G-A
• chr17-80104852-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PP3 PM2_Supporting PM3 PP4_Moderate BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.266G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 89 (p.Arg89His). Two individuals with this variant have been reported to exhibit clinical symptoms of infantile onset Pompe disease, one of them on enzyme replacement therapy (PMID:22644586 25626711) (PP4_Moderate). One of them is homozygous for c.[266G>A, 546+45G>C] (PMID:22644586), and the other is compound heterozygous for c.266G>A and c.104T>C (p.Phe35Ser) (PMID:25626711). The clinical significance of c.[266G>A, 546+45G>C] and c.104T>C (p.Phe35Ser) is unknown. The variant was also found in compound heterozygosity with c.2237G>C (p.Trp746Ser) (LP based on classification by the ClinGen Lysosomal Diseases VCEP) by exome sequencing in a proband, confirmed in trans; three siblings have the same genotype. Three of the siblings have GAA activity consistent with late onset disease, and GAA activity was slightly above this range in the remaining sibling. However, none of them have developed clinical symptoms of Pompe disease yet (see ClinVar Variation ID: 283219; SCV003927052.1). Individuals identified by newborn screen, and so far clinically asymptomatic, have the genotype c.-32-13T>G/c.266G>A; c.1377C>G (PMID:33202836); or are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.1655T>C (p.Leu552Pro) (PMID:33202836) or c.525delT (PMID:28196920). Another individual, with dual molecular diagnoses of GSD 1, and Pompe is homozygous for c.266G>A (p.Arg89His) but no clinical details are available (PMID:28600779). Therefore, without reports of any symptomatic individuals who have this variant in trans with a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v2.1.1 is 0.001168 in the Ashkenazi Jewish population (12/10272; no homozygotes). The highest population minor allele frequency in a continental population in gnomAD v2.1.1. is 0.00016 (5/30550) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.819 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). When expressed in COS cells, this variant was classified as Class E ("presumably nonpathogenic") by Kroos et al, 2012 (PMID:22644586). This includes 43.5% GAA activity in cells and 20% in medium, and is normally synthesized (though less than normal) and processed on Western blot (BS3_Supporting). Three other missense variants at the same position have been reported - c.265C>T (p.Arg89Cys) (VUS based on classification by the ClinGen LD VCEP; ClinVar Variation ID: 456412, SCV002817439.1), c.265C>A (p.Arg89Ser) (ClinVar Variation ID: 1989151), and c.266G>T (p.Arg89Leu) (ClinVar Variation ID: 2754338) (not yet classified by the ClinGen LD VCEP).There is a ClinVar entry for this variant (Variation ID: 283219). In summary, this variant meets the criteria to be classified as a Variant of Unknown Significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PP4_Moderate, PP3, PM2_Supporting, BS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 16, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814833/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:12
• Conservation: PhyloP100: 9.79
• Publications: 20 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: Uncertain_significance. The variant received 5 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.
• BS3: 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.266G>A	p.Arg89His	missense	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.266G>A	p.Arg89His	missense	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.266G>A	p.Arg89His	missense	Exon 2 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.266G>A	p.Arg89His	missense	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.266G>A	p.Arg89His	missense	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.266G>A	p.Arg89His	missense	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000141 AC: 35 AN: 248182 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1460536 Hom.: 1 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 726566

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000447 AC: 2 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86218

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52306

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1111898

Other (OTH) AF: 0.000282 AC: 17 AN: 60378

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000231 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000742 AC: 9

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	7	-	Glycogen storage disease, type II (12)
-	5	-	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.99
MPC		0.60
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.86
Mutation Taster		=7/93	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: rs200586324; hg19: chr17-78078651;