rs776948121
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000152.5(GAA):c.1941C>A(p.Cys647Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C647C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000152.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1941C>A | p.Cys647Ter | stop_gained | 14/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1941C>A | p.Cys647Ter | stop_gained | 14/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458150Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725018
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Mar 10, 2023 | The NM_000152.5:c.1941C>A (p.Cys647Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individual with Pompe disease. However, there is a ClinVar entry for this variant (Variation ID: 663894). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2018 | This sequence change creates a premature translational stop signal (p.Cys647*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GAA-related disease. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at