chr17-80112001-T-C
Variant summary
Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PM2_SupportingPS3_ModeratePM3PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.1655T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 552 (p.Leu552Pro). More than 10 individuals diagnosed with Pompe disease have been reported with this variant including at least 7 probands for whom laboratory data is published showing GAA activity in the deficient range (PMID 12923862, 18285536, 25681614, 27666774)(PP4_Moderate). Eight of these individuals were compound heterozygous for the variant and a pathogenic variant, phase unknown in all cases (PMID 12923862, 18285536, 18607768, 20033296, 25681614, 29122469 29422078, and two individuals were homozygotes (PMID 27666774)(PM3_Very strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In two functional studies, this variant has been shown to result in significantly decreased GAA activity (<5%) and abnormal processing when expressed in COS cells (PMIDs 14695532, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 279811, 2 star review status) with nine submitters all classifying the variant as pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3.(Classification approved August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815429/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1655T>C | p.Leu552Pro | missense_variant | 12/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1655T>C | p.Leu552Pro | missense_variant | 12/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152102Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250910Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135734
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461506Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727106
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152102Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74300
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:11
Pathogenic, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | Aug 03, 2023 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Leu552Pro variant in GAA has been reported in 26 individuals (including 5 Italian, 5 Brazilian, 4 German, 2 Spanish, and 2 Greek individuals) with Glycogen Storage Disease II, segregated with disease in 6 affected relatives from 3 families (PMID: 12923862, 19862843, 12213618, 22658377, 16838077, 18285536, 25681614, 16917947, 14695532, 17616415, 18607768, 19588081, 24158270, 23160972), and has also been reported pathogenic (by GeneDx, EGL, Counsyl, and Integrated Genetics/Laboratory Corporation of America) in ClinVar (Variation ID: 279811). This variant has been identified in 0.007% (8/111590) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs779556619). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Leu552Pro variant may impact GAA processing, levels, and activity (PMID: 14695532, 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Leu552Pro variant is pathogenic (PMID: 12923862, 12213618, 16838077, 18285536, 25681614, 16917947, 24158270; Variation ID: 371622, 550327, 550355). The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Glycogen Storage Disease II with <10% GAA activity detected in their muscle, lymphocyte, and muscle cells (PMID: 16917947, 12213618, 20033296, 12923862, 27666774, 19046416, 16838077, 24158270, 25681614, 18285536). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with likely pathogenic and pathogenic variants in Glycogen Storage Disease II and in vitro functional studies with COS cells transfected with this variant. ACMG/AMP Criteria applied: PM3, PS3, PM2, PP3, PP4 (Richards 2015). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 02, 2016 | Variant summary: The GAA c.1655T>C (p.Leu552Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120282 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant has been identified in many Pompe patients in the literature in homozygous and compound heterozygous state. In at least one patient with a compound heterozygous genotype, leukocyte GAA enzyme residual activity was 18.78% of normal, indicating that this variant has significantly reduced activity. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 19, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 552 of the GAA protein (p.Leu552Pro). This variant is present in population databases (rs779556619, gnomAD 0.006%). This missense change has been observed in individuals with Pompe disease (PMID: 14695532, 17616415, 18607768, 19588081, 20638881, 24158270, 25681614, 27666774). ClinVar contains an entry for this variant (Variation ID: 279811). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 17213836, 19862843, 25036864, 25409744). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Aug 02, 2024 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Sep 07, 2021 | The NM_000152.5: c.1655T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 552 (p.Leu552Pro). More than 10 individuals diagnosed with Pompe disease have been reported with this variant including at least 7 probands for whom laboratory data is published showing GAA activity in the deficient range (PMID 12923862, 18285536, 25681614, 27666774)(PP4_Moderate). Eight of these individuals were compound heterozygous for the variant and a pathogenic variant, phase unknown in all cases (PMID 12923862, 18285536, 18607768, 20033296, 25681614, 29122469 29422078, and two individuals were homozygotes (PMID 27666774)(PM3_Very strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In two functional studies, this variant has been shown to result in significantly decreased GAA activity (<5%) and abnormal processing when expressed in COS cells (PMIDs 14695532, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 279811, 2 star review status) with nine submitters all classifying the variant as pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3. (Classification approved August 17, 2021) - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2024 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2023 | Identified in multiple unrelated individuals with Pompe disease in published literature (Bodamer et al., 2002; Palermo et al., 2012; Remiche et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect (Flanagan et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11949932, 22658377, 27862019, 25681614, 14695532, 18285536, 34530085, 31254424, 24158270, 22990675, 25036864, 23668440, 27666774, 25052852, 19588081, 16917947, 18607768, 29422078, 31086307, 34426522, 33560568, 33202836, 34852371, 19862843, 25687635, 12213618) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 26, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 20, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at