17-80107837-T-G

Position:

• chr17-80107837-T-G

Variant summary

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

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 ENST00000302262.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.85

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.896T>G	p.Leu299Arg	missense_variant	5/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.896T>G	p.Leu299Arg	missense_variant	5/20	1	NM_000152.5	ENSP00000305692	P1

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:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2020	This variant is not present in population databases (ExAC no frequency). 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 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. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 11, 2022	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. -

Glycogen storage disease type II, infantile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0295);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

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: rs121907940; hg19: chr17-78081636;