17-80112594-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000152.5(GAA):c.1771C>T(p.Arg591Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,692 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1771C>T | p.Arg591Trp | missense_variant | 13/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1771C>T | p.Arg591Trp | missense_variant | 13/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248660Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135278
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460692Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 726688
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 12, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces arginine with tryptophan at codon 591 of the GAA protein (p.Arg591Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs770983413, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of Pompe disease (PMID: 26830551). ClinVar contains an entry for this variant (Variation ID: 551782). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 15, 2020 | The p.Arg591Trp variant in GAA has been reported in one Caucasian individual with glycogen storage disease II (PMID: 25673129, 26830551) and has been identified in 0.002% (2/111876) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770983413). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg591Trp variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 18, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at