17-80108700-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000152.5(GAA):c.1198G>A(p.Val400Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,612,592 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V400V) has been classified as Likely benign.
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.1198G>A | p.Val400Ile | missense_variant | 8/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1198G>A | p.Val400Ile | missense_variant | 8/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000524 AC: 13AN: 247946Hom.: 0 AF XY: 0.0000593 AC XY: 8AN XY: 134936
GnomAD4 exome AF: 0.0000370 AC: 54AN: 1460394Hom.: 0 Cov.: 38 AF XY: 0.0000440 AC XY: 32AN XY: 726500
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74354
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 400 of the GAA protein (p.Val400Ile). This variant is present in population databases (rs758334520, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 566063). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. 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, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | Has not been previously reported in peer-reviewed literature as pathogenic or benign to our knowledge. However, in an abstract by Dib et al. (2014), p.(V400I) was reported in a mother and daughter with a distal myopathy presentation, however a second GAA variant was not reported.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Dib_2014_Abstract) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | GAA: PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 12, 2020 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2023 | The p.V400I variant (also known as c.1198G>A), located in coding exon 7 of the GAA gene, results from a G to A substitution at nucleotide position 1198. The valine at codon 400 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at