chr17-80108488-G-C

Position:

• chr17-80108488-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PP4_Moderate PVS1 PM3

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

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1076-1G>C		splice_acceptor_variant, intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1076-1G>C		splice_acceptor_variant, intron_variant		1	NM_000152.5	ENSP00000305692.3

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 07, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2021	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in the inclusion of intron 6 and intron 7 (PMID: 16917947). Experimental studies have shown that disruption of this splice site affects GAA function (PMID: 17616415). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Disruption of this splice site has been observed in individuals with glycogen storage disease type II (PMID: 16917947, 17616415). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 6 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the gain of 56 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

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
GERP RS		4.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555600050; hg19: chr17-78082287;