rs1055945806
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_SupportingPS1_SupportingPVS1_StrongPP4_ModeratePM3
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.-32-3C>A variant is located in the splice acceptor region of intron 1 and has been shown to impact splicing. In fibroblasts from an individual with Pompe disease who was compound heterozygous for the variant and a missense variant in GAA, RT-PCR revealed loss of exon 2 (p.M1_T182del, which includes the 27 residues of signal sequence, the 42 residues of the propeptide and the first 113 amino acids of the mature protein (from 70 to 182) (PMID:18429042). A later study, in which the variant was expressed in a minigene, showed that the variant results in about 20% of transcripts with normal splicing of exon 2 (of note, this is a slightly lower level of normal splicing than observed for a well known pathogenic variant in the same splice region, c.-32-13T>G). Abnormal splicing events included complete loss of exon 2 (r.-32_546del) and activation of a cryptic splice site (r.‐32_486del) (PMID:31301153). Due to loss of a critical region (the signal sequence) in aberrantly spliced transcripts, but with presence of some normal transcript (albeit at a lower level than a known pathogenic variant in the same splice region), PVS1 was applied at the strong level (PMID:37352859) (PVS1_Strong, PS1_Supporting applied based on recommendations in PMID:37352859). This variant has been reported in at least 6 probands with late onset Pompe disease including two individuals with documented GAA activity <30% normal in fibroblasts (PMID:19046416, 21550241) (PP4_Moderate). Two of these probands have been reported to have this variant in compound heterozygosity, phase unknown, with another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.1655T>C (p.Leu552Pro) (PMID:18429042) and c.482_483del (PMID:21550241). In addition, three affected siblings have been reported to be homozygous for the variant (PMID:19588081, 20464284, 25681614) (PM3). Another three patients are compound heterozygous for the variant and a missense variant (either c.1905C>A (p.Asn635Lys), c.1447G>A (p.Gly483Arg), or c.2173C>T (p.Arg725Trp)) (PMID:19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.0. is 0.000007314 (8/1093866 alleles) in the European non-Finnish populationn, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371662). 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 (Specifications Version 2.0): PVS1_Strong, PM3, PS1_Supporting, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041878/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GAA | NM_000152.5 | c.-32-3C>A | splice_region_variant, intron_variant | ENST00000302262.8 | NP_000143.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GAA | ENST00000302262.8 | c.-32-3C>A | splice_region_variant, intron_variant | 1 | NM_000152.5 | ENSP00000305692.3 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000559 AC: 8AN: 1430012Hom.: 0 Cov.: 30 AF XY: 0.00000424 AC XY: 3AN XY: 707696
GnomAD4 genome
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 09, 2022 | Variant summary: Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 3' acceptor site. Goina_2019 have shown c.-32-3C>A and -32-3C>G results in exon 2 skipping. The variant was absent in 233126 control chromosomes (gnomAD). c.-32-3C>A has been reported in multiple individuals homozygous and compound heterozygous affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and this variant was segregated with disease in at least one family (examples: Oba-Shinjo_2009 and Grzesiuk_2010). The variant also segregated with the disease. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 28, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 09, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 18429042). ClinVar contains an entry for this variant (Variation ID: 371622). This variant has been observed in individuals with glycogen storage disease type II (PMID: 18429042, 19588081, 20464284). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and is likely to result in the loss of the initiator methionine. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Nov 21, 2023 | The NM_000152.5:c.-32-3C>A variant is located in the splice acceptor region of intron 1 and has been shown to impact splicing. In fibroblasts from an individual with Pompe disease who was compound heterozygous for the variant and a missense variant in GAA, RT-PCR revealed loss of exon 2 (p.M1_T182del, which includes the 27 residues of signal sequence, the 42 residues of the propeptide and the first 113 amino acids of the mature protein (from 70 to 182) (PMID: 18429042). A later study, in which the variant was expressed in a minigene, showed that the variant results in about 20% of transcripts with normal splicing of exon 2 (of note, this is a slightly lower level of normal splicing than observed for a well known pathogenic variant in the same splice region, c.-32-13T>G). Abnormal splicing events included complete loss of exon 2 (r.-32_546del) and activation of a cryptic splice site (r.‐32_486del) (PMID: 31301153). Due to loss of a critical region (the signal sequence) in aberrantly spliced transcripts, but with presence of some normal transcript (albeit at a lower level than a known pathogenic variant in the same splice region), PVS1 was applied at the strong level (PMID: 37352859) (PVS1_Strong, PS1_Supporting applied based on recommendations in PMID: 37352859). This variant has been reported in at least 6 probands with late onset Pompe disease including two individuals with documented GAA activity <30% normal in fibroblasts (PMID: 19046416, 21550241) (PP4_Moderate). Two of these probands have been reported to have this variant in compound heterozygosity, phase unknown, with another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.1655T>C (p.Leu552Pro) (PMID: 18429042) and c.482_483del (PMID: 21550241). In addition, three affected siblings have been reported to be homozygous for the variant (PMID: 19588081, 20464284, 25681614) (PM3). Another three patients are compound heterozygous for the variant and a missense variant (either c.1905C>A (p.Asn635Lys), c.1447G>A (p.Gly483Arg), or c.2173C>T (p.Arg725Trp)) (PMID: 19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.0. is 0.000007314 (8/1093866 alleles) in the European non-Finnish populationn, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371662). 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 (Specifications Version 2.0): PVS1_Strong, PM3, PS1_Supporting, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at