rs786204614

chr17-80104929-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000152.5(GAA):c.343C>T(p.Gln115Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 0.0660

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80104929-C-T is Pathogenic according to our data. Variant chr17-80104929-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 188996.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80104929-C-T is described in Lovd as [Pathogenic]. Variant chr17-80104929-C-T is described in Lovd as [Pathogenic]. Variant chr17-80104929-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.343C>T	p.Gln115Ter	stop_gained	2/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.343C>T	p.Gln115Ter	stop_gained	2/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Gln115Ter variant in GAA was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 4027), in one individual with myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 4027), however the phase of these variants is unknown at this time. The p.Gln115Ter variant in GAA has been previously reported in at least two unrelated individuals with glycogen storage disease II (PMID: 17616415, PMID: 17041744). These two affected individuals were compound heterozygotes who carried pathogenic or likely pathogenic in trans (PMID: 17616415, PMID: 17041744, ClinVar Variation ID: 982297, 1353052), which increases the likelihood that the p.Gln115Ter variant in GAA is pathogenic. This variant has also been reported in ClinVar (Variation ID: 188996) and has been interpreted as likely pathogenic by Counsyl and the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 115, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015). -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 07, 2023	The NM_000152.5(GAA):c.343C>T (p.Gln115Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least three individuals have been reported to have Pompe disease and this variant (PMIDs 17041744, 17616415, 32528171). GAA activity is reduced in the patients for whom it was reported (13-35% normal) but PP4 was not applied because the activity does not meet the strict thresholds specified by the ClinGen LD VCEP. ONe of these individuals is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1076-1G>C, phase unknown (PMID: 17616415). Two additional reports describe a child who is compound heterozygous for the variant and p.Pro482Leu (PMID: 17041744, 17616415). The allelic data will be used in the classification of p.Pro482Leu and is not included here to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 188996). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.13	N
MutationTaster	Benign	1.0	A;A
Vest4		0.64
GERP RS		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs786204614; hg19: chr17-78078728;