chr17-80107837-T-G

Variant names:

• chr17-80107837-T-G
• rs121907940
• NM_000152.5:c.896T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PM3_Supporting PM5 PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.896T>G variant in GAA is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 299 (p.Leu299Arg). This variant has been detected in 1 individual with Pompe disease. This individual was compound heterozygous for the variant and a pathogenic variant, an exon 18 deletion previously assessed by the ClinGen LSD VCEP (PMID:7603531,7717400) (PM3_Supporting). The patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts, but exact values for the patient's GAA activity and laboratory control values for GAA activity were not provided and PP4 could not be applied (PMID:7717400). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity, indicating that this variant may impact protein function (PMID:19862843), meeting criteria for PS3_Supporting. Expression of the variant in TR4219 cells in a separate study resulted in "complete loss of GAA activity" (PMID:7717400). REVEL Score = 0.93 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 4025, 1 star review status) with 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this 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 (specifications Version 2.0): PM5, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA116601/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.85
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.896T>G	p.Leu299Arg	missense	Exon 5 of 20	NP_000143.2
	GAA	NM_001079803.3		c.896T>G	p.Leu299Arg	missense	Exon 6 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.896T>G	p.Leu299Arg	missense	Exon 5 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.896T>G	p.Leu299Arg	missense	Exon 5 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.896T>G	p.Leu299Arg	missense	Exon 6 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.896T>G	p.Leu299Arg	missense	Exon 5 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Apr 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Leu299Arg and p.Leu299Pro) in affected individuals suggests that this may be a clinically significant residue (PMID: 25752415, 7717400). This variant has been reported to affect GAA protein function (PMID: 7717400, 19862843). Additionally, 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. This variant has been observed in individuals affected with Pompe disease (PMID: 7717400, Invitae). ClinVar contains an entry for this variant (Variation ID: 4025). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 299 of the GAA protein (p.Leu299Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine.

May 11, 2022

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.896T>G variant in GAA is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 299 (p.Leu299Arg). This variant has been detected in 1 individual with Pompe disease. This individual was compound heterozygous for the variant and a pathogenic variant, an exon 18 deletion previously assessed by the ClinGen LSD VCEP (PMID:7603531,7717400) (PM3_Supporting). The patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts, but exact values for the patient's GAA activity and laboratory control values for GAA activity were not provided and PP4 could not be applied (PMID:7717400). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity, indicating that this variant may impact protein function (PMID:19862843), meeting criteria for PS3_Supporting. Expression of the variant in TR4219 cells in a separate study resulted in "complete loss of GAA activity" (PMID:7717400). REVEL Score = 0.93 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 4025, 1 star review status) with 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this 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 (specifications Version 2.0): PM5, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0295)
MVP		1.0
MPC		0.65
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.98
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs121907940; hg19: chr17-78081636;