rs786204661
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000152.5(GAA):c.365del(p.Met122ArgfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Consequence
GAA
NM_000152.5 frameshift
NM_000152.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.158
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-80104950-AT-A is Pathogenic according to our data. Variant chr17-80104950-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 189059.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.365del | p.Met122ArgfsTer20 | frameshift_variant | 2/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.365del | p.Met122ArgfsTer20 | frameshift_variant | 2/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 33
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74352
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 25, 2020 | Variant summary: GAA c.365delT (p.Met122ArgfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247798 control chromosomes (gnomAD v2). c.365delT has been reported in the literature in a compound heterozygous individual who was affected with the late onset form of Glycogen Storage Disease, Type 2 (Pompe Disease), where the other variant found in trans was the common disease variant, c.-32-13T>G, that is associated with the late-onset form of the disorder (Bernstein_2010). This publication also reported that the enzyme activity measured in patient derived cultured fibroblasts was about 5-7% of the normal (Bernstein_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Aug 19, 2021 | NM_000152.5:c.365del (p.Met122ArgfsTer20) variant in GAA is a frameshift 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). One patient with late onset Pompe disease has been reported with documentation of laboratory values showing GAA deficiency (~7% lower limit of normal) in cultured fibroblasts (2 points) and who is on enzyme replacement therapy (1 point)(PMID: 20638881). (Total 3 points, PP4_Moderate). This patient is compound heterozygous, with unknown phase, for the variant and a pathogenic variant in GAA, c.-32-13T>G (0.5 points, PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 189059, two star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. 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 LSD VCEP (Specification Version 2.0): PVS1, PP4_Moderate, PM3_Supporting, PM2_Supporting. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 25, 2021 | This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met122Argfs*20) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in combination with another GAA variant in an individual affected with severe, later onset Pompe disease (PMID: 20638881). ClinVar contains an entry for this variant (Variation ID: 189059). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at