rs1057517165
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4PM3PVS1PM2
This summary comes from the ClinGen Evidence Repository: This variant, c.236_246del (p.Pro79ArgfsTer13), has been reported in multiple patients with Pompe disease. For two of these patients, residual GAA activity is reported and meets the ClinGen LSD VCEP's specifications for PP4 (PMID 17056254, 30778879). Both of these patients are compound heterozygous for the variant and a unique pathogenic variant; one with c.377G>A (p.Trp126Ter), in trans (PMID 17056254), and the other with c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). This data meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). There is a ClinVar entry for this variant (Variation ID: 371302, 1 star review status) with 1 submitter classifying the variant as pathogenic. 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 LSD VCEP: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041880/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.236_246del | p.Pro79ArgfsTer13 | frameshift_variant | 2/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.236_246del | p.Pro79ArgfsTer13 | frameshift_variant | 2/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Pro79Argfs*13) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 17056254). ClinVar contains an entry for this variant (Variation ID: 371302). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Jun 16, 2020 | This variant, c.236_246del (p.Pro79ArgfsTer13), has been reported in multiple patients with Pompe disease. For two of these patients, residual GAA activity is reported and meets the ClinGen LSD VCEP's specifications for PP4 (PMID 17056254, 30778879). Both of these patients are compound heterozygous for the variant and a unique pathogenic variant; one with c.377G>A (p.Trp126Ter), in trans (PMID 17056254), and the other with c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). This data meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). There is a ClinVar entry for this variant (Variation ID: 371302, 1 star review status) with 1 submitter classifying the variant as pathogenic. 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 LSD VCEP: PVS1, PM2, PM3, PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 23, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at