17-80108488-G-C

Variant names:

• chr17-80108488-G-C
• rs1555600050
• NM_000152.5:c.1076-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PM3 PP4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1076-1G>C variant in GAA occurs within the canonical splice acceptor site of intron 6. RT-PCR of fibroblast RNA from a patient who is heterozygous for the variant revealed the inclusion of 79 bp of intron 6 and and 89 bp of intron 7 into the transcript, which is predicted to lead to a frameshift and nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID:16917947) (PVS1). Six patients have been reported including one who is homozygous for the variant with symptoms consistent with infantile onset Pompe disease and documentation of deficient GAA activity meeting the specifications of the ClinGen LD VCEP, two compound heterozygous patients with later onset symptoms and documentation of deficient GAA activity, and three patients with symptoms of Pompe disease and re[ported to have reduced GAA activity but for whom individual residual GAA activity was not provided or did not meet criteria (PMID:16917947, 17616415) (PP4_Moderate). This variant was the second most common variant in a Spanish cohort with Pompe disease, accounting for 6/44 alleles (14%) (PMID:17616415). One patient is compound heterozygous for the variant and another pathogenic variant in GAA, c.-32-13T>G, phase unknown, 0.5 points (PMID:16917947), and one patient is homozygous for the variant, 0.5 points (PMID:17616415). Another four patients are compound heterozygous for the variant and another GAA variant. The allelic data from these patients will be used in the assessment of the second variant and it not included here to avoid circular logic (PMID:17616415). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1353052). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (specifications version 2.0): PVS1, PP4_Moderate, PM3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401364879/MONDO:0009290/010

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GAA NM_000152.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.29
• Publications: 2 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: 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.
• 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.1076-1G>C		splice_acceptor intron	N/A	NP_000143.2
	GAA	NM_001079803.3		c.1076-1G>C		splice_acceptor intron	N/A	NP_001073271.1
	GAA	NM_001079804.3		c.1076-1G>C		splice_acceptor intron	N/A	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1076-1G>C		splice_acceptor intron	N/A	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1076-1G>C		splice_acceptor intron	N/A	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.1076-1G>C		splice_acceptor intron	N/A	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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 Cov.: 38

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Glycogen storage disease, type II (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.3
GERP RS		4.8
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.82		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555600050; hg19: chr17-78082287;