17-80108537-G-T

Position:

• chr17-80108537-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS3_Supporting PP3 PP4_Moderate PM3_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1124G>T (p. Arg375Leu) variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 375. This variant has been detected in at least 4 individuals with Pompe disease. Of those, at least 2 patients with late onset Pompe disease from Italy are documented, with reduced GAA activity in leukocytes or muscle. These patients are compound heterozygous, phase unknown, for c.1124G>T (p.Arg375Leu) and the pathogenic variant c.-32-13T>G i(PMIDs: 24158270, 22081099). One proband with severe infantile Pompe was reported to be compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed in trans, and another patient with infantile-onset Pompe disease was homozygous for the variant (PM3_Strong; PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001787 (2/111942 alleles) in the European (non-Finnish) population, which is lower than threshold for PM2_Supporting (<0.001), meeting PM2_Supporting. Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity (PMID:18429042) (PS3_supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7 (PP3). Another missense variant [c.1124G>A (p.Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID:21757382, 21484825) . However this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is ClinVar entry for the variant (Variation ID: 283230, two star review status) with six submitters classifying the variant as Pathogenic/Likely Pathogenic. In summary, c.1124G>T (p.Arg375Leu) variant meets the criteria to be classified as likely pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PM3_strong ; PP4_Moderate; PS3_supporting; PM2_Supporting, PP3. (Classification approved by the ClinGen LSD VCEP on December 6, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815178/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 7.56

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 Likely_pathogenic. Variant got 9 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.1124G>T	p.Arg375Leu	missense_variant	7/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1124G>T	p.Arg375Leu	missense_variant	7/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248456 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460556 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 726574

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

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	Baylor Genetics	Mar 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 375 of the GAA protein (p.Arg375Leu). 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 Pompe disease (PMID: 18429042, 22990675, 24158270, 29422078). ClinVar contains an entry for this variant (Variation ID: 283230). 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: 18429042). This variant disrupts the p.Arg375 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21757382), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg375Leu variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22081099, 24158270, 25103075, 25396301, 18429042) and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 283230). This variant has been identified in 0.002% (2/111942) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142752477). 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 a GAA-deficient human fibroblast cell line provide some evidence that the p.Arg375Leu variant may impact GAA production and activity (PMID: 18429042). 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 2 pathogenic variants curated by our study in individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Arg375Leu variant is pathogenic (PMID: 22081099, 24158270, 25103075, 25396301, 18429042). The phenotype of 3 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity in muscle tissue <10% of normal, consistent with disease (PMID: 24158270, 22081099). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Supporting, PM2, PP3, PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2022	Variant summary: GAA c.1124G>T (p.Arg375Leu) 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 8e-06 in 248456 control chromosomes. c.1124G>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Parenti_2007). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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 20, 2022	The NM_000152.5:c.1124G>T (p. Arg375Leu) variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 375. This variant has been detected in at least 4 individuals with Pompe disease. Of those, at least 2 patients with late onset Pompe disease from Italy are documented, with reduced GAA activity in leukocytes or muscle. These patients are compound heterozygous, phase unknown, for c.1124G>T (p.Arg375Leu) and the pathogenic variant c.-32-13T>G i(PMIDs: 24158270, 22081099). One proband with severe infantile Pompe was reported to be compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed in trans, and another patient with infantile-onset Pompe disease was homozygous for the variant (PM3_Strong; PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001787 (2/111942 alleles) in the European (non-Finnish) population, which is lower than threshold for PM2_Supporting (<0.001), meeting PM2_Supporting. Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity (PMID: 18429042) (PS3_supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7 (PP3). Another missense variant [c.1124G>A (p.Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID: 21757382, 21484825) . However this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is ClinVar entry for the variant (Variation ID: 283230, two star review status) with six submitters classifying the variant as Pathogenic/Likely Pathogenic. In summary, c.1124G>T (p.Arg375Leu) variant meets the criteria to be classified as likely pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PM3_strong ; PP4_Moderate; PS3_supporting; PM2_Supporting, PP3. (Classification approved by the ClinGen LSD VCEP on December 6, 2022) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 13, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 11, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.95		Loss of MoRF binding (P = 0.0472);Loss of MoRF binding (P = 0.0472);
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142752477; hg19: chr17-78082336;