rs763359208
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_ModeratePM2_SupportingPM3_StrongPVS1_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.2815_2816del (p.Val939LeufsTer78) variant in GAA is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. The frameshift begins at amino acid 939; the normal GAA gene product is 952 amino acids in length. Hence <10% of the normal product is missing. The impact of adding an abnormal sequence of 78 amino acids to the C terminus of GAA, due to the frameshift, is unknown (PVS1_Moderate). At least 8 patients with this variant who have been diagnosed with Pompe disease have been described including 2 patients for whom residual GAA activity was provided and was either <1% normal in cultured skin fibroblasts (PMID 22538254) or below the normal range in dried blood spots (https://doi.org/10.3390/metabo11070446). One of these patients and at least 2 additional patients were on enzyme replacement therapy (PMID 22538254, 25316892, 32373469, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf) (PP4_Moderate). The reported patients include compound heterozygotes for the variant and another pathogenic/likely pathogenic variant in GAA including for c.118C>T (p.Arg40Ter) (PMID 24269976, ClinVar SCV SCV001371737.1), c.1935C>A (p.Asp645Glu) (PMIDs 32373469, 28394184, 22538254), c.2238G>C (p.Trp746Cys) (PMID 25316892, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf,), and c.2585delG (PMID 28394184)(PM3_Strong). Another patient has been reported as compound heterozygous for the variant and c.266G>T (p.Arg89Leu) (https://doi.org/10.3390/metabo11070446). The in trans data from this patient will be used for the assessment of p.Arg89Leu and is not included here in order to avoid circular logic. For another patient described with Pompe disease and the variant, the second GAA variant was not identified (PMID 10338092). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001631 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371481, 2 star review status) with 2 submitters classifying the variant as pathogenic and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PM3_Strong, PVS1_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen LSD VCEP - Oct.19.2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CV371481/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GAA | NM_000152.5 | c.2815_2816del | p.Val939LeufsTer78 | frameshift_variant | 20/20 | ENST00000302262.8 | NP_000143.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GAA | ENST00000302262.8 | c.2815_2816del | p.Val939LeufsTer78 | frameshift_variant | 20/20 | 1 | NM_000152.5 | ENSP00000305692 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251298Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461778Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727202
GnomAD4 genome
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:5Uncertain:1
| Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The heterozygous p.Val939LeufsTer78 variant in GAA has been reported in 2 Malaysian individuals with Glycogen Storage Disease II (Wahab, Yakob, and Jalil, 2013), and has also been reported pathogenic by Counsyl in ClinVar (Variation ID: 371481). This variant has been identified in 0.0174% (3/17242) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057517308). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 939 and leads to a premature termination codon 78 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2 (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 04, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2022 | Variant summary: GAA c.2815_2816delGT (p.Val939LeufsX78) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 1.2e-05 in 251298 control chromosomes. c.2815_2816delGT has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic n=2, likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Nov 19, 2021 | The NM_000152.5: c.2815_2816del (p.Val939LeufsTer78) variant in GAA is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. The frameshift begins at amino acid 939; the normal GAA gene product is 952 amino acids in length. Hence <10% of the normal product is missing. The impact of adding an abnormal sequence of 78 amino acids to the C terminus of GAA, due to the frameshift, is unknown (PVS1_Moderate). At least 8 patients with this variant who have been diagnosed with Pompe disease have been described including 2 patients for whom residual GAA activity was provided and was either <1% normal in cultured skin fibroblasts (PMID 22538254) or below the normal range in dried blood spots (https://doi.org/10.3390/metabo11070446). One of these patients and at least 2 additional patients were on enzyme replacement therapy (PMID 22538254, 25316892, 32373469, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf) (PP4_Moderate). The reported patients include compound heterozygotes for the variant and another pathogenic/likely pathogenic variant in GAA including for c.118C>T (p.Arg40Ter) (PMID 24269976, ClinVar SCV SCV001371737.1), c.1935C>A (p.Asp645Glu) (PMIDs 32373469, 28394184, 22538254), c.2238G>C (p.Trp746Cys) (PMID 25316892, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf,), and c.2585delG (PMID 28394184)(PM3_Strong). Another patient has been reported as compound heterozygous for the variant and c.266G>T (p.Arg89Leu) (https://doi.org/10.3390/metabo11070446). The in trans data from this patient will be used for the assessment of p.Arg89Leu and is not included here in order to avoid circular logic. For another patient described with Pompe disease and the variant, the second GAA variant was not identified (PMID 10338092). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001631 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371481, 2 star review status) with 2 submitters classifying the variant as pathogenic and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PM3_Strong, PVS1_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen LSD VCEP - Oct.19.2021) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change results in a frameshift in the GAA gene (p.Val939Leufs*78). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the GAA protein and extend the protein by 63 additional amino acid residues. This variant is present in population databases (rs763359208, gnomAD 0.02%). This frameshift has been observed in individuals with Pompe disease (PMID: 21757382, 24269976, 28394184, 29122469). ClinVar contains an entry for this variant (Variation ID: 371481). 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