rs786204303

chr17-80117015-G-Cchr17-80117015-G-Tchr17-80117015-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.2237G>C(p.Trp746Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,514 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W746C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.45

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 strand (size 4) in uniprot entity LYAG_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) 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 chr17-80117016-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 265160.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-80117015-G-C is Pathogenic according to our data. Variant chr17-80117015-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80117015-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2237G>C	p.Trp746Ser	missense_variant	16/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2237G>C	p.Trp746Ser	missense_variant	16/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000678 AC: 17 AN: 250744 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135734

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461216 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726926

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74466

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000203 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 746 of the GAA protein (p.Trp746Ser). This variant is present in population databases (rs752921215, gnomAD 0.03%). This missense change has been observed in individuals with Pompe disease (PMID: 18425781, 22081099). ClinVar contains an entry for this variant (Variation ID: 188484). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 23430493). This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18458862, 21232767, 21757382, 23430493, 25093132, 25526786, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The p.Trp746Ser variant in GAA has been reported at least 3 individuals with glycogen storage disorder type II (GSD type II), two of whom were compound heterozygous with the variant a pathogenic variant on the other allele and also carried another variant (p.Gln743Arg) in cis (on the same allele as this variant) (Kroos 2008 PMID: 18425781, Liu 2013 PMID: 24169249, Preisler 2017 PMID: 28490439). It has also been identified in 0.03% (5/15284) of Latino/Admixed American chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 188484). In vitro functional studies suggest the variant impairs protein function (Kroos 2012 PMID: 22644586, Niño 2013 PMID: 23430493). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Several variants involving this codon (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) have been identified in individuals with GSD type II and have been classified as pathogenic in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive glycogen storage disorder type II. ACMG/AMP criteria applied: PM5_Strong, PM2_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics	May 05, 2023	The classification of the variant was performed according to the recommendations of ClinGen lysosomal storage disorders variant curation expert panel (Guidelines version 2, specific for the GAA gene). The NM_000152.5:c.2237G>C p.(Trp746Ser) is a missense variant that replaces a highly conserved Trp with Ser. This variant is present at a very low frequency in gnomAD databases (ƒExomes = 0.0000678, ƒgenomes = 0.0000854), only in heterozygosity and meets the PM2_Supporting criterion (1pt). This variant is located in a mutational hot-spot sequence of 17 amino-acids length with 20 missense/in-frame variants (8 pathogenic variants, 12 uncertain variants) and without benign variation, which qualifies the c.2237G>C variant as moderate pathogenic (PM1 criterion, 2pts). Five pathogenic alternative variants [Trp746Cys (chr17:78090815G>T and chr17:78090815 G>C), Trp746Leu, Trp746Gly and Trp746Arg] affecting the same amino acid (Trp746) have been reported in association with disease in ClinVar (PM5_strong: 4pts). Multiple lines of computational evidence strongly support the pathogenicity of this variant (REVEL score: 0.919) and therefore meets the PP3 criterion (supporting, 1pt). The c.2237G>C variant confirmed to be in trans with different pathogenic or likely pathogenic variants (PMID: 25526786, PMID: 18429042, PMID: 12923862, PMID: 21484825, PMID: 16917947, PMID: 18285536) in individuals with Pompe disease, thus meets the PM3_very strong criterion (4pts). In vitro functional studies provide evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). In our study, the four individuals (with c.[266G>A];[2237G>C] genotype, 2-13 years) were found to have GAA activity clearly within the patient range (1.1-4.9nmol/h/mg) in leukocytes using 4-methylumbelliferyl-α-D-glucoside as a substrate. Using glycogen as a substrate, the GAA activity was found to be within the range for LOPD patients (3-10nmol/h/mg) for one subject and slightly above the upper limit for the three subjects. The presence of the KM-mutant polymorphism c.271G>A and the pseudodeficiency variant c.[1726G>A (p.Gly576Ser); 2065G>A (p.Glu689Lys)] was excluded. Based on the ClinGen LSD VCEP's specifications, this data meets PP4_Moderate rule (2pts). In summary, this variant meets the criteria to be classified as a pathogenic variant (total 14 pts) for Pompe disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2023	Variant summary: GAA c.2237G>C (p.Trp746Ser) 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 6.8e-05 in 250744 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (6.8e-05 vs 0.0042), allowing no conclusion about variant significance. c.2237G>C has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Angelini_2012). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Trp746Ser variant in GAA has been reported in 1 Danish, 1 Chinese, 1 Northern European, and 6 Italian individuals with Glycogen Storage Disease II (PMID: 28490439, 24169249, 18425781, 22081099), and has been identified in 0.032% (8/24924) of African chromosomes and 0.011% (4/35424) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and Shahid Beheshti University of Medical Sciences in ClinVar (Variation ID: 188484). In vitro functional studies provide some evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). 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 a reported pathogenic variant in 6 individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ser variant is pathogenic (PMID: 22081099). The phenotype of 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in muscle tissue, consistent with disease (PMID: 22081099). Four additional variants (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) at the the same position, including a reported pathogenic variant, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 265160, 556431, 499293, 284776). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II and functional evidence. ACMG/AMP Criteria applied: PS3, PM5, PM3_supporting, PM2, PP3, PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2022	Published functional studies demonstrate that p.(W746S) results in a significant reduction in enzymatic activity (Kroos et al., 2012; Nino et al., 2013); 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: 24444888, 24169249, 18425781, 22644586, 23430493, 29325298, 30275481, 19343043, 22253258, 31589614, 27535533, 34906458, 26582918, 34020684, 33717985, 22081099, Jian2021, 33344388) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-14	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.94		Gain of glycosylation at W746 (P = 0.0151);Gain of glycosylation at W746 (P = 0.0151);
MVP		0.97
MPC		0.69
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.93

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: rs752921215; hg19: chr17-78090814;