rs201185475
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM3PM2PP4_ModeratePVS1
This summary comes from the ClinGen Evidence Repository: This variant, c.172C>T (p.Gln58Ter), is a nonsense variant, predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The variant is not in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic variant in two patients who meet the ClinGen LSD VCEP's PP4 specifications; one with c.525delT, confirmed in trans (PMID 10377006), and the other with c.841C>T (p.Arg281Trp), identified in a clinical diagnostic laboratory. This data meets PM3. Of note, pseudodeficiency variants are absent in the latter patient, allowing PP4_Moderate to be applied. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 20817528). There is a ClinVar entry for this variant (Variation ID: 188903, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274104/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.172C>T | p.Gln58Ter | stop_gained | 2/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.172C>T | p.Gln58Ter | stop_gained | 2/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458718Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 725588
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152336Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74492
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Apr 20, 2020 | This variant, c.172C>T (p.Gln58Ter), is a nonsense variant, predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The variant is not in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic variant in two patients who meet the ClinGen LSD VCEP's PP4 specifications; one with c.525delT, confirmed in trans (PMID 10377006), and the other with c.841C>T (p.Arg281Trp), identified in a clinical diagnostic laboratory. This data meets PM3. Of note, pseudodeficiency variants are absent in the latter patient, allowing PP4_Moderate to be applied. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 20817528). There is a ClinVar entry for this variant (Variation ID: 188903, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4_Moderate. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 06, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 25, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188903). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 10377006). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln58*) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at