17-80113282-G-T

Variant names:

• chr17-80113282-G-T
• rs398123172
• NM_000152.5:c.2105G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_Moderate PM3_Strong PP3 PS3_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2105G>T variant in GAA is a missense variant predicted tocause substitution of arginine by leucine at amino acid 702 (p.Arg702Leu). It has been reported in at least two unrelated patients with infantile-onset Pompe disease with documented GAA deficiency and receiving enzyme replacement therapy, and in one patient identified via newborn screening with deficient confirmatory enzyme in blood and clinical symptoms (Clinical diagnostic laboratory) described has having late-onset Pompe disease, meeting criteria for PP4_moderate (PMID:26497565, 27344650, 26167453). Of those individuals, a a proband and full sibling were compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen LD VCEP, c.2512C>T (p.Gln838Ter) (ClinVar Variation ID: Variation ID: 92479, SCV001371718.1), confirmed in trans by parental testing (PMID:26167453) (1 point). Another patient was compound heterozygous for the variant and variant classified as pathogenic by the ClinGen LD VCEP, c.1798C>T (p.Arg600Cys) (Variation ID: 640911; SCV002032136.1), phase unknown (PMID:26497565, 27344650). The variant has also been reported in trans with a pathogenic variant (c.-32-13T>G; ClinVar Variation ID: 4027) in one individual identified on newborn screening with deficient confirmatory GAA and clinical symptoms with deficient confirmatory GAA in DBS (Clinical diagnostic laboratory) (PM3_Strong).It has also been reported in one individual with a positive newborn screen for Pompe disease and deficient confirmatory GAA activity, but no reported phenotype (PMID:33202836). It is absent from large population databases (gnomAD v2.1.1.) meeting PM2_Supporting. Expression of the variant in COS-7 and HEK293T cells resulted in 0.4% GAA activity in cells and 1.3% in medium and evidence of abnormal GAA synthesis and processing – leading the variant to be classified as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID:22644586), meeting PS3_moderate. The computational predictor REVEL gives a score of 0.972 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 92472). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): (PM3_strong, PP4_moderate, PS3_moderate, PM2_supporting, PP3).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220396/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 9.74

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 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.
• 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 rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.2105G>T	p.Arg702Leu	missense_variant	Exon 15 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2105G>T	p.Arg702Leu	missense_variant	Exon 15 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 34

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448060 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 719012

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4

Apr 30, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.2105G>T (p.Arg702Leu) 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 was absent in 222484 control chromosomes (gnomAD). c.2105G>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; examples Bali_2012, Stenger_2015, Broomfield_2016, Reuser_2019). 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 enzyme activity in vitro (Kroos_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.2105G>T variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 702 (p.Arg702Leu). It has been reported in at least two unrelated patients with infantile-onset Pompe disease with documented GAA deficiency and receiving enzyme replacement therapy, and in one patient identified via newborn screening with deficient confirmatory enzyme in blood and clinical symptoms (Clinical diagnostic laboratory) described has having late-onset Pompe disease, meeting criteria for PP4_moderate (PMID: 26497565, 27344650, 26167453). Of those individuals, a a proband and full sibling were compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen LD VCEP, c.2512C>T (p.Gln838Ter) (ClinVar Variation ID: Variation ID: 92479, SCV001371718.1), confirmed in trans by parental testing (PMID: 26167453) (1 point). Another patient was compound heterozygous for the variant and variant classified as pathogenic by the ClinGen LD VCEP, c.1798C>T (p.Arg600Cys) (Variation ID: 640911; SCV002032136.1), phase unknown (PMID: 26497565, 27344650). The variant has also been reported in trans with a pathogenic variant (c.-32-13T>G; ClinVar Variation ID: 4027) in one individual identified on newborn screening with deficient confirmatory GAA and clinical symptoms with deficient confirmatory GAA in DBS (Clinical diagnostic laboratory) (PM3_Strong). It has also been reported in one individual with a positive newborn screen for Pompe disease and deficient confirmatory GAA activity, but no reported phenotype (PMID: 33202836). It is absent from large population databases (gnomAD v2.1.1.) meeting PM2_Supporting. Expression of the variant in COS-7 and HEK293T cells resulted in 0.4% GAA activity in cells and 1.3% in medium and evidence of abnormal GAA synthesis and processing – leading the variant to be classified as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID:22644586), meeting PS3_moderate. The computational predictor REVEL gives a score of 0.972 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 92472). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): (PM3_strong, PP4_moderate, PS3_moderate, PM2_supporting, PP3). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). -

Feb 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg702 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18211760, 18425781, 26310554). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 92472). This missense change has been observed in individual(s) with infantile onset Pompe disease (PMID: 22252923, 27344650, 29122469). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 702 of the GAA protein (p.Arg702Leu). -

not provided Pathogenic:1

Jun 19, 2013

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.2	H;H
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.92		Gain of methylation at K697 (P = 0.0424);Gain of methylation at K697 (P = 0.0424);
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.98

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: rs398123172; hg19: chr17-78087081;