chr17-80113350-C-T

Position:

• chr17-80113350-C-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2173C>T variant in GAA is a missense variant predicted to cause substitution of Arg by Trp at amino acid 725 (p.Arg725Trp). This variant is present in gnomAD V2.1.1 with the highest population minor allele frequency of 0.00077 (7/9058 alleles) in the Ashkenazi Jewish population, which is lower than the ClinGen LSD VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.909 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. This variant results in 6.5% GAA activity when expressed in COS cells (PMID:8401535), meeting the ClinGen LSD VCEP specifications for PS3. This variant has been detected in at least 12 individuals with Pompe disease. Of those individuals, 10 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant including 2 with c.573C>A-pathogenic (PMID:30155607), 1 with ex18 deletion-pathogenic (PMID:28648663), 3 with c.-32-13T>G-pathogenic (PMID:27711114, 17616415), 1 with c.-32-3C>A-likely pathogenic (PMID:19588081), 2 with c.1076-1G>C pathogenic variants (PMID:17616415). 1 individual was homozygous for the variant (PMID:27711114). A total of 4.25 points were awarded. Thus meets PM3-Very Strong. At least 4 individuals have been reported with this variant and GAA activity <10% normal in leukocytes/muscle samples or <30% normal in cultured fibroblasts. Patient 5 (PMID:21550241) has 0.2% normal GAA activity in fibroblast. Patient 3 has 1.1% normal GAA activity in fibroblasts, patient 15 has 5.2% normal GAA activity in fibroblasts (PMID:17616415). Patient 1 (PMID:3865697) has GAA activity in affected range in muscle, cultured fibroblasts, and leucocytes when compared to the laboratory’s control range. This meets the criteria for PP4. There is a ClinVar entry for this variant (Variation ID: 4024; 2 star review status) with 9 submitters classifying the variant as pathogenic with no conflict. In summary, this variant meets the criteria to be classified as 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): PS3-supporting, PM2-supporting, PM3-very strong, PP3, and PP4-moderate.(Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 3, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116598/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.17

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.2173C>T	p.Arg725Trp	missense_variant	15/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2173C>T	p.Arg725Trp	missense_variant	15/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000389 AC: 8 AN: 205684 Hom.: 0 AF XY: 0.00000902 AC XY: 1 AN XY: 110808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000684

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000223

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 21 AN: 1432526 Hom.: 0 Cov.: 33 AF XY: 0.00000987 AC XY: 7 AN XY: 709352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000356

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000456

Gnomad4 OTH exome AF: 0.0000677

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 725 of the GAA protein (p.Arg725Trp). This variant is present in population databases (rs121907938, gnomAD 0.08%). This missense change has been observed in individual(s) with Pompe disease (PMID: 8401535, 17616415, 19588081, 21550241, 28648663). ClinVar contains an entry for this variant (Variation ID: 4024). 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: 8401535, 21972175). This variant disrupts the p.Arg725 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 18458862), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Oct 03, 2023	The NM_000152.5:c.2173C>T variant in GAA is a missense variant predicted to cause substitution of Arg by Trp at amino acid 725 (p.Arg725Trp). This variant is present in gnomAD V2.1.1 with the highest population minor allele frequency of 0.00077 (7/9058 alleles) in the Ashkenazi Jewish population, which is lower than the ClinGen LSD VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.909 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. This variant results in 6.5% GAA activity when expressed in COS cells (PMID: 8401535), meeting the ClinGen LSD VCEP specifications for PS3. This variant has been detected in at least 12 individuals with Pompe disease. Of those individuals, 10 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant including 2 with c.573C>A-pathogenic (PMID: 30155607), 1 with ex18 deletion-pathogenic (PMID: 28648663), 3 with c.-32-13T>G-pathogenic (PMID: 27711114, 17616415), 1 with c.-32-3C>A-likely pathogenic (PMID: 19588081), 2 with c.1076-1G>C pathogenic variants (PMID: 17616415). 1 individual was homozygous for the variant (PMID: 27711114). A total of 4.25 points were awarded. Thus meets PM3-Very Strong. At least 4 individuals have been reported with this variant and GAA activity <10% normal in leukocytes/muscle samples or <30% normal in cultured fibroblasts. Patient 5 (PMID: 21550241) has 0.2% normal GAA activity in fibroblast. Patient 3 has 1.1% normal GAA activity in fibroblasts, patient 15 has 5.2% normal GAA activity in fibroblasts (PMID: 17616415). Patient 1 (PMID: 3865697) has GAA activity in affected range in muscle, cultured fibroblasts, and leucocytes when compared to the laboratory’s control range. This meets the criteria for PP4. There is a ClinVar entry for this variant (Variation ID: 4024; 2 star review status) with 9 submitters classifying the variant as pathogenic with no conflict. In summary, this variant meets the criteria to be classified as 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): PS3-supporting, PM2-supporting, PM3-very strong, PP3, and PP4-moderate. (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 3, 2023) -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2016	Variant summary: The GAA c.2173C>T (p.Arg725Trp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/44258 control chromosomes at a frequency of 0.0000226, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in at least 5 patients with Pompe disease (3 juvenile and 2 adult). Functional studies showed GAA p.R725W had less than 10% residual activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 15, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Arg725Trp variant in GAA has been reported in 6 individuals (including 3 Spanish and 1 Brazilian individuals) in the compound heterozygous state with Glycogen Storage Disease II (PMID: 21550241, 8401535, 17616415, 19588081). This variant has also been reported likely pathogenic by Counsyl and pathogenic by Integrated Genetics, Invitae, and OMIM in ClinVar (Variation ID: 4024). This variant has been identified in 0.077% (7/9058) of Ashkenazi Jewish chromosomes and 0.002% (2/104918) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907938). 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 with HEK and COS cells provide some evidence that the p.Arg725Trp variant may impact GAA activity (PMID: 21972175, 8401535). 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 confirmed in trans with a pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg725Trp variant is pathogenic (PMID: 8401535). The phenotype of heterozygotes with this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in relevant tissues (PMID: 17616415, 8401535, 21550241). 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 with transfected cells and multiple occurrences with pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 03, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2023	Published functional studies found this variant is associated with significantly reduced enzyme activity (Hermans MM et al., 1993; Ebrahim HY et al., 2012); 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: 17616415, 28648663, 8401535, 19588081, 21550241, 31589614, 35302691, 19343043, 22253258, 31254424, 31342611, 22252923, 27711114, 34530085, 21972175) -

GLYCOGEN STORAGE DISEASE II, ADULT FORM Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.97		Gain of catalytic residue at A724 (P = 0.0129);Gain of catalytic residue at A724 (P = 0.0129);
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.96

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: rs121907938; hg19: chr17-78087149; COSMIC: COSV56408105; COSMIC: COSV56408105;