rs549029029

chr17-80112666-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.1843G>A(p.Gly615Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. G615E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 9.80

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr17-80112667-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 972758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-80112666-G-A is Pathogenic according to our data. Variant chr17-80112666-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188786.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80112666-G-A is described in Lovd as [Pathogenic]. Variant chr17-80112666-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1843G>A	p.Gly615Arg	missense_variant	13/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1843G>A	p.Gly615Arg	missense_variant	13/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 243962 Hom.: 0 AF XY: 0.00000751 AC XY: 1 AN XY: 133124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000222

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459872 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). 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. ClinVar contains an entry for this variant (Variation ID: 188786). This missense change has been observed in individual(s) with Pompe disease (PMID: 10338092, 15366815, 16860134, 18458862, 18607768, 21757382, 24269976, 25037089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs549029029, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 615 of the GAA protein (p.Gly615Arg). -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly615Arg variant in GAA has been reported in 13 individuals (including 4 Taiwanese, 1 Chinese, and 1 German individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 16860134, 18458862, 10338092, 24269976, 21232767, 20080426, 15366815, 18607768, 21757382, 25037089), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 188786). This variant has been identified in 0.022% (4/17994) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549029029). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Gly615Arg variant may impact protein function (PMID: 19862843). However, these types of assays may not accurately represent biological function. 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 combination with reported pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly615Arg variant is pathogenic (PMID: 16860134, 18458862). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21757382, 16860134, 18458862). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies, low frequency in the general population, and multiple occurrences in combination with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2018	Variant summary: GAA c.1843G>A (p.Gly615Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 97298 control chromosomes (gnomAD and publication). The variant, c.1843G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), whom presented with significantly decreased enzyme activity (<10%). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 06, 2022	The NM_000152.5: c.1843G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 615 (p.Gly615Arg). At least 7 patients with a diagnosis of Pompe disease have been reported with this variant. Five of these patients are reported to have infantile onset Pompe disease (IOPD) and meet the criteria for PP4_Moderate with <10% GAA activity in cultured fibroblasts and/or GAA activity in the affected range in leukocytes (PMIDs: 15366815, 16860134, 18458862, 25037089), documented symptoms consistent with IOPD, and on enzyme replacement therapy (PMIDs: 16860134, 25037089) (PP4_Moderate). Of the reported patients, three are compound heterozygous, phase unknown, for another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, either c.2238G>A (p.Trp746Ter) (PMID: 16860134) or c.1935C>A (p.Asp645Glu) (PMID: 18458862) (2 patients). Two patients are homozygous for the variant (PMID: 15366815, 25037089) (PM3_Strong). A further two patients are compound heterozygous for the variant and either c.1832G>A (p.Gly611Asp) (PMID: 24269976) or c.1933G>C (p.Asp645His (clinical laboratory data) . The allelic data from these patients will be used in the classification of the other variant and is not included here to avoid circular. Finally, An 4 patients have been reported in the literature but the data was not included because the cDNA change for the variant was not provided, or does not match amino acid change (PMIDs: 10338092, 18607768, 21757382). The highest population minor allele frequency in gnomAD is 0.00022 in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant resulted in <2% GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 188746, 2 star review status), with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Verions 2.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 13, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18458862, 21757382, 24269976, 11738358, 31254424, 15366815, 18301443, 20080426, 12394636, 16860134, 19862843, 11949932, 29046207, 31953985, 30275481, 32711049, 32014045, 31086307, 21232767, 10338092, 18607768) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.2	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.97		Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);
MVP		1.0
MPC		0.59
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		0.97

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: rs549029029; hg19: chr17-78086465;