chr17-80118731-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000152.5(GAA):c.2725G>A(p.Val909Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
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: 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250678Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135622
GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461020Hom.: 1 Cov.: 33 AF XY: 0.0000784 AC XY: 57AN XY: 726816
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74474
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:5
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 909 of the GAA protein (p.Val909Met). This variant is present in population databases (rs138407065, gnomAD 0.01%). This missense change has been observed in individual(s) with proximal muscle weakness and myopathy (PMID: 33250842). ClinVar contains an entry for this variant (Variation ID: 456414). 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. 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. -
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This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not provided Uncertain:3
Previously reported in association with Pompe disease, however detailed clinical information and biochemical testing were not reported (Reuser AJJ et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 456414; ClinVar); This variant is associated with the following publications: (PMID: 19343043, 22253258, 33250842, 33560568, 31342611) -
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not specified Uncertain:1
Variant summary: GAA c.2725G>A (p.Val909Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250678 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4e-05 vs 0.0042), allowing no conclusion about variant significance. c.2725G>A has been reported in the literature in individuals affected with Myopathy (examples: Guelly_2020 and Chakravorty_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at