rs536906561

Positions:

• chr17-80112929-G-A

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_Supporting PP4_Moderate PP3 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1942G>A (p.Gly648Ser) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v2.1.1 of 0.00034 (10/29720 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 18 patients with a diagnosis of Pompe disease have been reported with this variant including those with documented deficient GAA activity and/or symptoms consistent with infantile onset Pompe disease and/or on enzyme replacment therapy (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962) (PP4_Moderate). In a study of the Maroon population of French Guiana, 9 out of 15 probands with "enzymatically confirmed" infantile onset Pompe disease were compound heterozygous for c.1942G>A (p.Gly648Ser) and c.2560C>T (p.Arg854Ter), a variant which has been classified as pathogenic by the ClinGen LD VCEP. The two variants are assumed to be in trans based on the high carrier frequency of both variants in that population. The carrier frequency of c.1942G>A (p.Gly648Ser) was 1 in 47 (9/425 women tested) (PMID:29637184). Patients have also been reported who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.2214G>A (p.Trp768Ter) (PMID:26575883) and c.-32-13T>G (2 patients, PMIDs: 17643989, 25455803, 27193587). In addition, at least 3 patients are homozygous for the variant (PMID:26497565, 29122469, 29889338, 30214072) (PM3_VeryStrong). Patients compound heterozygous for the variant and c.1076-22T>G (17643989, 25455803), c.2646+2T>A (PMID:29422078), and c.1099T>C (p.Trp367Arg) (PMID:31510962) have also been reported. However, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid circular logic. When expressed in SV40_immortalized GAA deficient fibroblasts, the enzyme activity was "negligible" (PMID:9535769), and when expressed in COS cells, the variant resulted in <2% wild type GAA activity (PMID:19862843) (PS3_Supporting). The score for the REVEL meta-predictor, 0.98, also supports that the variant has a deleterious impact on GAA function (PP3). Another amino acid substitution at the same position has been reported in at least one individual with Pompe disease c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument). There is a ClinVar entry for this variant (Variation ID: 188902). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274102/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 9.82

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 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1942G>A	p.Gly648Ser	missense_variant	14/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1942G>A	p.Gly648Ser	missense_variant	14/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000536 AC: 13 AN: 242472 Hom.: 0 AF XY: 0.0000758 AC XY: 10 AN XY: 131908

Gnomad AFR exome AF: 0.0000660

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000915

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1458310 Hom.: 0 Cov.: 33 AF XY: 0.0000290 AC XY: 21 AN XY: 725154

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: 0.000280

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000825 AC: 10

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:10

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly648Ser variant in GAA has been reported in 15 individuals with Glycogen Storage Disease II (PMID: 29637184, 17573812, 26497565, 17643989, 25455803, 9535769), and has also been reported pathogenic by Invitae and likely pathogenic by Counsyl in ClinVar (Variation ID: 188902). This variant has been identified in 0.034% (10/29720) of South Asian chromosomes in gnomAD chromosomes in gnomAD by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs536906561). 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.Gly648Ser variant may impact GAA activity (PMID: 9535769). 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 the homozygous state and in combination with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly648Ser variant is pathogenic (PMID: 29637184, 17573812, 26497565, 17643989, 25455803, 9535769). Individuals with this variant in the homozygous and heterozygous state and a phenotype highly specific for disease based on assays of GAA activity in relevant tissue (PMID: 29637184, 17573812, 26497565, 9535769). One additional likely pathogenic variant resulting in a different amino acid change at the same position, p.Gly648Asp, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 22644586). 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 and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PM5_Supporting, PP3, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jun 22, 2023	The homozygous mis-sense variant c.1942G>A (p.Gly648Ser) has been identified in a proband with dilated cardiomyopathy, respiratory distress, muscle weakness, difficulty in sitting from lying position, proximal muscle weakness in upper and lower extremities. This variant has been found 0.0054%gnomAD (aggregated). This has been previously reported PMID: 18429042 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 648 of the GAA protein (p.Gly648Ser). This variant is present in population databases (rs536906561, gnomAD 0.03%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 9535769, 17643989, 26575883). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188902). 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: 9535769, 19862843). This variant disrupts the p.Gly648 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 22644586, 23146291), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 25, 2023	A Heterozygous variation in exon 14 of the GAA gene that results in the amino acid substitution of serine for glycine at codon 648 was detected. The observed variant c.1942G>A (p.Gly648Ser) has not been reported in the 1000 genomes database and this variant has minor allele frequency of 0.0054% in gnomAD database. The in silico prediction of the variant are possibly damaging by PolyPhen-2, SIFT, CAAD and MutationTaster. In summary, the variant meets our criteria to be 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.1942G>A (p.Gly648Ser) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v2.1.1 of 0.00034 (10/29720 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 18 patients with a diagnosis of Pompe disease have been reported with this variant including those with documented deficient GAA activity and/or symptoms consistent with infantile onset Pompe disease and/or on enzyme replacment therapy (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962) (PP4_Moderate). In a study of the Maroon population of French Guiana, 9 out of 15 probands with "enzymatically confirmed" infantile onset Pompe disease were compound heterozygous for c.1942G>A (p.Gly648Ser) and c.2560C>T (p.Arg854Ter), a variant which has been classified as pathogenic by the ClinGen LD VCEP. The two variants are assumed to be in trans based on the high carrier frequency of both variants in that population. The carrier frequency of c.1942G>A (p.Gly648Ser) was 1 in 47 (9/425 women tested) (PMID: 29637184). Patients have also been reported who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.2214G>A (p.Trp768Ter) (PMID: 26575883) and c.-32-13T>G (2 patients, PMIDs: 17643989, 25455803, 27193587). In addition, at least 3 patients are homozygous for the variant (PMID: 26497565, 29122469, 29889338, 30214072) (PM3_VeryStrong). Patients compound heterozygous for the variant and c.1076-22T>G (17643989, 25455803), c.2646+2T>A (PMID: 29422078), and c.1099T>C (p.Trp367Arg) (PMID: 31510962) have also been reported. However, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid circular logic. When expressed in SV40_immortalized GAA deficient fibroblasts, the enzyme activity was "negligible" (PMID: 9535769), and when expressed in COS cells, the variant resulted in <2% wild type GAA activity (PMID: 19862843) (PS3_Supporting). The score for the REVEL meta-predictor, 0.98, also supports that the variant has a deleterious impact on GAA function (PP3). Another amino acid substitution at the same position has been reported in at least one individual with Pompe disease c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument). There is a ClinVar entry for this variant (Variation ID: 188902). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023) -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2019	Variant summary: GAA c.1942G>A (p.Gly648Ser) results in a non-conservative amino acid change in the Glycoside hydrolase superfamily (IPR017853) of 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 5.5e-05 in 237998 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (5.5e-05 vs 0.0042), allowing no conclusion about variant significance. c.1942G>A has been reported in the literature in multiple individuals affected with adult onset and infantile onset Glycogen Storage Disease, Type 2 (Pompe Disease)(Huie_1998, Elenga_2018). A patient diagnosed with adult onset Pompe Disease was observed to have <10% enzyme activity in vivo. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2023	Published functional studies demonstrate a damaging effect through reduced enzyme function (Huie et al., 1998); Classified as a pathogenic variant by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (ClinVar 526521); This variant is associated with the following publications: (PMID: 33301762, 30275481, 26575883, 29637184, 33741225, 22253258, 19343043, 9535769, 19862843, 25455803, 27193587, 29122469, 22644586, 30214072, 31510962, 35833019, 16478160, 23146291, 17573812, 29422078, 26497565, 17643989) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs536906561; hg19: chr17-78086728; COSMIC: COSV56412369; COSMIC: COSV56412369;