rs543360994

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2_SupportingPM3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.781G>A variant in GAA is a missense variant predicted to cause substitution of Ala by Thr at amino acid 261 (p.Ala261Thr). One patient with infantile-onset Pompe disease who was homozygous for this variant has been reported;, the parents were confirmed to be heterozygous (PMID 31510962) (PM3_Supporting). The patients symptoms included dyspnea, poor feeding, failure to thrive, delayed motor milestone, short PR interval, biventricular hypertrophy, and severe intellectual disability. GAA activity was 0.43% of normal (PMID 31510962)(PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (3/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant results in reduced GAA activity (66% in cell extract and 5% in culture medium comparing to wildtype) and is classified as class D for the severity rating (PMID 31510962) (BS3_Supporting). The computational predictor REVEL gives a score of 0.584 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The computational splicing predictor SpliceAI predicts no impact on splicing. Two different missense variants, c.781G>C (p.Ala261Pro) and c.782C>T (p.Ala261Val) in the same codon have been reported in patients with Pompe disease. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 456438). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specification Version 2.0): PM2_supporting, PM3_supporting, PP4_Moderate, BS3_supporting.(Classification approved by the ClinGen LSD VCEP on Nov 1, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815016/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:4

Conservation

PhyloP100: 9.85

Publications

11 publications found

Variant links:

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

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAA	NM_000152.5	MANE Select	c.781G>A	p.Ala261Thr	missense	Exon 4 of 20	NP_000143.2	P10253
GAA	NM_001079803.3		c.781G>A	p.Ala261Thr	missense	Exon 5 of 21	NP_001073271.1	P10253
GAA	NM_001079804.3		c.781G>A	p.Ala261Thr	missense	Exon 4 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAA	ENST00000302262.8	TSL:1 MANE Select	c.781G>A	p.Ala261Thr	missense	Exon 4 of 20	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.781G>A	p.Ala261Thr	missense	Exon 5 of 21	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.781G>A	p.Ala261Thr	missense	Exon 4 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251028

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460800

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (4)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.6

PhyloP100

9.8

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.021

Polyphen

0.90

Vest4

0.61

MVP

0.98

MPC

0.35

ClinPred

0.76

GERP RS

5.1

Varity_R

0.67

gMVP

0.83

Mutation Taster

=30/70

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over