17-80112622-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000152.5(GAA):c.1799G>T(p.Arg600Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R600C) has been classified as Pathogenic.
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460678Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 726680
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74348
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 16, 2024 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 600 of the GAA protein (p.Arg600Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 17723315). 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%. This variant disrupts the p.Arg600 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338092, 19862843, 20033296, 30155607, 31342611). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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