17-80117015-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PM2_SupportingPM5
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2237G>T variant in GAA is a missense variant predicted to cause substitution of tryptophan by leucine at amino acid 746 (p.Trp746Leu). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001102 (7/63508 alleles) in the European Finnish population, which is lower than the ClinGen Lysosomal Diseases threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.832 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.2238G>C, p.Trp746Cys) (ClinVar Variation ID 265160) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). Three additional different missense variants (c.2237G>C, p.Trp746Ser; c.2236T>C, p.Trp746Arg; and c.2236T>G, p.Trp746Gly), in the same codon have been reported in patients with Pompe disease (ClinVar Variation IDs 188484, 499293, 556431). However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP. There is a ClinVar entry for this variant (Variation ID: 284776). In summary, there is currently insufficient evidence to determine the pathogenicity of this variant, and it meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM5, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815663/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000718 AC: 18AN: 250744Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135734
GnomAD4 exome AF: 0.0000664 AC: 97AN: 1461216Hom.: 0 Cov.: 30 AF XY: 0.0000729 AC XY: 53AN XY: 726926
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152298Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74466
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:1Uncertain:3
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This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 746 of the GAA protein (p.Trp746Leu). This variant is present in population databases (rs752921215, gnomAD 0.01%). This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (PMID: 23430949). ClinVar contains an entry for this variant (Variation ID: 284776). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7981676, 9535769, 21232767, 21757382, 25093132, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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not provided Uncertain:2
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at