chr17-80117092-T-C

Position:

• chr17-80117092-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PP4 PS3_Moderate PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2314T>C variant in GAA is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 772 (p.Trp772Arg). This variant has been detected in at least 1 individual with Pompe disease that was compound heterozygous for the variant and a pathogenic variant (PMID:31619483, 18757064) (PM3_Supporting). At least 1 patient with this variant had documented GAA deficiency in leukocytes or fibroblasts was noted to have deficient GAA activity but results were not provided and was reported to be eligible for enzyme replacement therapy for Pompe disease (PMID:31619483, 18757064) (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 5% wild type GAA activity and evidence of abnormal GAA synthesis and processing leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID:18425781) (PS3_Moderate). The computational predictor REVEL gives a score of 0.93 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: 552527; 1 star review status) with 1 submitter classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PS3_Moderate, PM2_Supporting, PP3, PP4, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401324918/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 7.51

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 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2314T>C	p.Trp772Arg	missense_variant	16/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2314T>C	p.Trp772Arg	missense_variant	16/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:1 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 19, 2022	The NM_000152.5:c.2314T>C variant in GAA is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 772 (p.Trp772Arg). This variant has been detected in at least 1 individual with Pompe disease that was compound heterozygous for the variant and a pathogenic variant (PMID: 31619483, 18757064) (PM3_Supporting). At least 1 patient with this variant had documented GAA deficiency in leukocytes or fibroblasts was noted to have deficient GAA activity but results were not provided and was reported to be eligible for enzyme replacement therapy for Pompe disease (PMID: 31619483, 18757064) (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 5% wild type GAA activity and evidence of abnormal GAA synthesis and processing leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 18425781) (PS3_Moderate). The computational predictor REVEL gives a score of 0.93 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: 552527; 1 star review status) with 1 submitter classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PS3_Moderate, PM2_Supporting, PP3, PP4, PM3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	.;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.1	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-14	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.97		Gain of catalytic residue at W772 (P = 0.0553);Gain of catalytic residue at W772 (P = 0.0553);
MVP		1.0
MPC		0.73
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555602703; hg19: chr17-78090891;