dbSNP rs121907942: GAA:p.Pro545Leu (chr17-80111023-C-T) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_000152.5(GAA):c.1634C>T(p.Pro545Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000992 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001338444: The most pronounced variant effect results in <10% of normal activity (Flanagan_2009)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P545S) has been classified as Likely pathogenic. The gene GAA is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.83

Publications

34 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001338444: The most pronounced variant effect results in <10% of normal activity (Flanagan_2009).; SCV002213638: Experimental studies have shown that this missense change affects GAA function (PMID: 7881422).

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in NM_000152.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-80111022-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1062425.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease due to acid maltase deficiency, late-onset.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 17-80111023-C-T is Pathogenic according to our data. Variant chr17-80111023-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1634C>T	p.Pro545Leu	missense splice_region	Exon 11 of 20	NP_000143.2	P10253
GAA	NM_001079803.3		c.1634C>T	p.Pro545Leu	missense splice_region	Exon 12 of 21	NP_001073271.1	P10253
GAA	NM_001079804.3		c.1634C>T	p.Pro545Leu	missense splice_region	Exon 11 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.1634C>T	p.Pro545Leu	missense splice_region	Exon 11 of 20	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.1634C>T	p.Pro545Leu	missense splice_region	Exon 12 of 21	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.1649C>T	p.Pro550Leu	missense splice_region	Exon 11 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250468

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.000226

AC:

AN:

53066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111910

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000270

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (5)

Glycogen storage disease due to acid maltase deficiency, late-onset (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.1

PhyloP100

5.8

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-9.9

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.54

MutPred

0.85

Loss of disorder (P = 0.0457)

MVP

1.0

MPC

0.55

ClinPred

1.0

GERP RS

5.5

Varity_R

0.91

gMVP

0.91

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

Splicevardb

2.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over