rs1344266804

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000152.5(GAA):c.2407C>T(p.Gln803Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000372 in 1,612,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q803Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAA
NM_000152.5 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 5.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-80117675-C-T is Pathogenic according to our data. Variant chr17-80117675-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 552368.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80117675-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2407C>T	p.Gln803Ter	stop_gained	17/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2407C>T	p.Gln803Ter	stop_gained	17/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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:

0.000478

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248496

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135010

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460416

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change creates a premature translational stop signal (p.Gln803*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 26572913). ClinVar contains an entry for this variant (Variation ID: 552368). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jul 03, 2023	The NM_000152.5:c.2407C>T (p.Gln803Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 (out of 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with late onset Pompe disease with this variant and treated by enzyme replacement therapy has been reported (PP4). This individual is compound heterozygous for the variant and "IVS 0-45T>G" (assumed to be c.-32-13T>G), a pathogenic variant in GAA, phase unknown (PMID: 26572913) (PM3_Supporting). Two additional patients have been reported to be compound heterozygous for p.Gln803Ter but the cDNA change provided is incorrect and thus this data was not included (PMID: 21940687). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 (1/111412 alleles) in the European-Non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 552368). 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 Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023) -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A

Vest4

0.88

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over