rs1057517105

chr17-80112655-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.1832G>A(p.Gly611Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G611S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 4.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr17-80112654-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 935199.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-80112655-G-A is Pathogenic according to our data. Variant chr17-80112655-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371226.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1832G>A	p.Gly611Asp	missense_variant	13/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1832G>A	p.Gly611Asp	missense_variant	13/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 01, 2016	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 06, 2022	The NM_000152.5:c.1832G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 611 (p.Gly611Asp). Four patients with a diagnosis of Pompe disease and this variant have been reported including two with documented features of infantile onset Pompe disease and laboratory values showing deficient GAA activity <1% in skin fibroblasts (PMID: 22252923) or in the affected range in dried blood spot assay (PMID: 25681614), and another reported with features consistent with infantile onset Pompe disease and deficient GAA activity but the laboratory value was not provided (PMID: 24269976). Finally, a patient with deficient GAA activity (level not known) was identified in clinical laboratory data (PP4_Moderate). Of the reported patients, three are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.2501_2502delCA, (pathogenic, presumed in trans, clinical laboratory data), c.1848dupC (clinical laboratory data) (pathogenic, phase unknown), and c.1843G>A (p.Gly615Arg) (PMID: 24269976) (likely pathogenic, phase unknown), and one patient is homozygous (PMID: 25681614). Another patient is compound heterozygous for the variant and c.1570A>T (p.Asn524Tyr). However, the allelic data from this patient with be used in the assessment of p.Asn524Tyr and is not included here to avoid circular logic. (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.821 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1831G>A, p.Gly611Ser) (ClinVar variation ID: 935199) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP. However, the data from c.1832 (p.Gly611Asp) was used in the classification of p.Gly611Ser, and therefore the data is not ncluded here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 371226, 1 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 611 of the GAA protein (p.Gly611Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease and reduced GAA enzymatic activity (PMID: 22252923, 24269976, 25681614; Invitae). ClinVar contains an entry for this variant (Variation ID: 371226). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly611Asp variant in GAA has been reported in 4 individuals (including 1 Chinese individual) with Glycogen Storage Disease II (PMID: 25681614, 22252923, 24269976), and has also been reported as a likely pathogenic variant by Counsyl and Invitae in ClinVar (Variation ID: 371226). This variant was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the p.Gly611Asp variant is pathogenic (PMID: 25681614). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA enzyme in a dried blood spot, consistent with disease (PMID: 25681614). In summary, the clinical significance of the p.Gly611Asp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3_Supporting, PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.87		Loss of MoRF binding (P = 0.0638);Loss of MoRF binding (P = 0.0638);
MVP		1.0
MPC		0.62
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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

Other links and lift over

dbSNP: rs1057517105; hg19: chr17-78086454;