17-80110793-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID:24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompedisease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815358/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251226Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135872
GnomAD4 exome AF: 0.0000800 AC: 117AN: 1461842Hom.: 0 Cov.: 37 AF XY: 0.0000756 AC XY: 55AN XY: 727224
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74320
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:8
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This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 502 of the GAA protein (p.Met502Val). This variant is present in population databases (rs376067362, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 24158270, 33202836; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 439746). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
The c.1504A>G (p.M502V) variant in the GAA gene has been reported in conjunction with another variant in an unaffected individual (PMID: 24158270) and in a newborn screen (PMID: 33202836). There is insufficient evidence at this time to determine the significance of this variant. -
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The heterozygous p.Met502Val variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 24158270). This variant has been identified in 0.010% (13/128968) of European (non-Finnish) chromosomes and 0.003% (1/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376067362). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by Invitae, EGL Genetic Diagnostics, Illumina, and ARUP Laboratories in ClinVar (Variation ID: 439746). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Methionine (Met) at position 502 is not highly conserved in mammals and evolutionary distant species, and one species (American alligator) carries a Valine (Val), raising the possibility that this change at this position may be tolerated. This variant was reported in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II (PMID: 24158270). In summary, the clinical significance of the p.Met502Val variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). -
The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID: 24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). -
not provided Uncertain:4
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Observed with a second variant in GAA in a patient with late-onset Pompe disease; the phase of these variants was not determined (PMID: 24158270); Observed with additional variants in GAA in a patient with low GAA activity on newborn screening (PMID: 33202836); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 22253258, 19343043, 30985853, 24158270, 33202836) -
PP3, PM2, PM3 -
not specified Uncertain:2
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Variant summary: GAA c.1504A>G (p.Met502Val) results in a conservative amino acid change located in the Glycoside hydrolase family 31, TIM barrel domain (IPR000322) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251226 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.4e-05 vs 0.0042), allowing no conclusion about variant significance. c.1504A>G has been reported in the literature in at least 2 individuals affected with or positive on a newborn screen for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Remiche_2014, Ficicioglu_2020). However, 2 unaffected individuals have been reported carrying this variant in trans with a pathogenic variant or pathogenic allele (c.-32-13T>G per Pompe disease variant database; [c.-32-13T>G;c.1856G>A] per ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect in patient cells results in 10%-<30% of normal activity (example, Remiche_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33202836, 24158270). ClinVar contains an entry for this variant (Variation ID: 439746). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at