rs778068209
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000152.5(GAA):c.1432G>A(p.Gly478Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G478G) has been classified as Likely benign.
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1432G>A | p.Gly478Arg | missense_variant | 9/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1432G>A | p.Gly478Arg | missense_variant | 9/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248486Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135182
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460582Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726636
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Gly478Arg variant in GAA has been reported in seven individuals with glycogen storage disease II (PMID: 28394184, 25213570, 25998610, 17616415, 14695532) and has also been reported as likely pathogenic by Counsyl in ClinVar (VariationID: 551295). This variant has been identified in 0.003% (1/34538) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778068209). 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 using COS cells transfected with the variant provide some evidence that the p.Gly478Arg variant may impact protein function (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. Additionally, this variant was reported in combination with reported pathogenic variants in individuals with glycogen storage disease II (VariationID: 4027, 194154, 403712; PMID: 25998610, 17616415, 28394184, 25213570). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PP4 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the GAA protein (p.Gly478Arg). This variant is present in population databases (rs778068209, gnomAD 0.003%). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 17616415, 25213570, 25998610, 28394184, 28592009). ClinVar contains an entry for this variant (Variation ID: 551295). 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. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 28592009). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 04, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at