rs778418246

Positions:

• chr17-80113002-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_Supporting PM3_Strong PS3_Supporting PM5_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2015G>A variant in GAA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 672 (p.Arg672Gln). At least 8 probands with Pompe disease have been reported with this variant, including 4 probands and one sibling with published data showing GAA activity below the normal range in muscle or cultured fibroblasts (PMID:9535769, 17092519, 33578445), three of whom also showed clinical improvement on enzyme replacement therapy (PMID 33578445)(PP4_Moderate). Five probands are homozygous for the variant (PMIDs 9535769, 25712382, 28937052, 33578445). Two probands are compound heterozygous for the variant and a pathogenic variant in GAA; the second variant is either c.118C>T (p.Arg40Ter)(ClinVar SCV001371737.1)(phase unknown), or c.1857C>G (p.Ser619Arg)(phase unknown)(PM3_Strong). Another proband is heterozygous for the variant with the second variant unidentified (PMID 11053688). When generated by site-directed mutagenesis and expressed in SV40-immortalized GAA deficient fibroblasts or COS cells, the variant resulted in very low (<2%) residual GAA activity (PMID 9535769, 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.955 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest population minor allele frequency in gnomAD is 0.0001107 (East Asian) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting (PM2_Supporting). Two other missense variants at the same amino acid position, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported in patients with Pompe disease, suggesting that this residue may be important in GAA function. Two other missense variants, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported at the same amino acid position; c.2014C>T (p.Arg672Trp) has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. PM5_Supporting is applied here because c.2014C>T (p.Arg672Trp) is only likely pathogenic without PM5 data from c.2015G>A (p.Arg672Gln), thus avoiding circular logic (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 371126, 2 star review status) with 3 submitters classifying the variant as pathogenic and one as likely pathogenic. 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 Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815566/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 9.86

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 10 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.
• PM5: 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.2015G>A	p.Arg672Gln	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.2015G>A	p.Arg672Gln	missense_variant	14/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000207 AC: 5 AN: 241788 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458548 Hom.: 0 Cov.: 33 AF XY: 0.00000827 AC XY: 6 AN XY: 725430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jun 22, 2023	The homozygous variant c.2015G>A (p.Arg672Gln) has been identified in homozygous state. Phenotypes observed in the proband were muscle weakness, difficulty in sitting from lying position, difficulty in standing from sitting position, hypotonia, proximal and distal muscle weakness in upper and lower extremities and positive gower sign. This variant has been previously reported PMID: 27858635. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2017	Variant summary: The GAA c.2015G>A (p.Arg672Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/237400 control chromosomes at a frequency of 0.0000211, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant has been reported in affected individuals in the literature in the homozygous and compound heterozygous state, and has been reported in homozygous patients to lead to complete loss of acid maltase activity (Tsujino_GAA_ND_2000). In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 672 of the GAA protein (p.Arg672Gln). 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 missense change has been observed in individual(s) with inherited muscular disorder and Pompe disease (PMID: 11053688, 23884227, 25712382, 27363342, 28592009). ClinVar contains an entry for this variant (Variation ID: 371126). 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. Experimental studies have shown that this missense change affects GAA function (PMID: 9535769, 19862843, 28592009). This variant disrupts the p.Arg672 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9535769, 15986226, 16917947, 19862843, 21484825, 21757382). 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. -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PS3,PM3_Strong, PM2, PP3,PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg672Gln variant in GAA has been reported in 7 individuals (including 4 Japanese and 1 Korean individuals) with Glycogen Storage Disease II, segregated with disease in 4 affected relatives from 2 families (PMID: 17092519, 11053688, 9535769, 25712382), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 371126). This variant has been identified in 0.011% (2/18064) of East Asian chromosomes, 0.003% (1/29862) of South Asian chromosomes, and 0.001% (1/108950) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778418246). 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.Arg672Gln variant may impact GAA activity (PMID: 9535769, 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 and activate a cryptic splice site, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported likely pathogenic variant, and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Arg672Gln variant is pathogenic (PMID: 17092519). The presence of this variant in the homozygous state in 4 individuals with Glycogen Storage Disease II also increases the likelihood that the p.Arg672Gln variant is pathogenic (PMID: 11053688, 9535769, 25712382). The phenotype of 4 individuals with this variant (including 2 homozygotes) is highly specific for Glycogen Storage Disease II based on assays that only detected residual GAA enzyme activity in muscle biopsy and/or cultured skin fibroblast cells (PMID: 11053688). One additional pathogenic variant at the the same position, p.Arg672Trp, has been curated by our study, supporting that a change at this position may not be tolerated. 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 in the homozygous state and the heterozygous state with a pathogenic variant in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PM5, PP3, PP4 (Richards 2015). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 04, 2022	The NM_000152.5:c.2015G>A variant in GAA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 672 (p.Arg672Gln). At least 8 probands with Pompe disease have been reported with this variant, including 4 probands and one sibling with published data showing GAA activity below the normal range in muscle or cultured fibroblasts (PMID: 9535769, 17092519, 33578445), three of whom also showed clinical improvement on enzyme replacement therapy (PMID 33578445)(PP4_Moderate). Five probands are homozygous for the variant (PMIDs 9535769, 25712382, 28937052, 33578445). Two probands are compound heterozygous for the variant and a pathogenic variant in GAA; the second variant is either c.118C>T (p.Arg40Ter)(ClinVar SCV001371737.1)(phase unknown), or c.1857C>G (p.Ser619Arg)(phase unknown)(PM3_Strong). Another proband is heterozygous for the variant with the second variant unidentified (PMID 11053688). When generated by site-directed mutagenesis and expressed in SV40-immortalized GAA deficient fibroblasts or COS cells, the variant resulted in very low (<2%) residual GAA activity (PMID 9535769, 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.955 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest population minor allele frequency in gnomAD is 0.0001107 (East Asian) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting (PM2_Supporting). Two other missense variants at the same amino acid position, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported in patients with Pompe disease, suggesting that this residue may be important in GAA function. Two other missense variants, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported at the same amino acid position; c.2014C>T (p.Arg672Trp) has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. PM5_Supporting is applied here because c.2014C>T (p.Arg672Trp) is only likely pathogenic without PM5 data from c.2015G>A (p.Arg672Gln), thus avoiding circular logic (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 371126, 2 star review status) with 3 submitters classifying the variant as pathogenic and one as likely pathogenic. 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 Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.97		Gain of disorder (P = 0.1665);Gain of disorder (P = 0.1665);
MVP		1.0
MPC		0.58
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs778418246; hg19: chr17-78086801;