17-80117015-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PM2_SupportingPM5PM3PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2237G>C variant in GAA is a missense variant predicted to result in the substitution of tryptophan by serine at amino acid 746 (p.Trp746Ser). This variant has been reported in at least 11 patients with late onset Pompe disease (LOPD) (PMID:18425781, 22081099, 24169249, 28490439, 33344388, 34020684), with two having GAA enzyme activity <10% in muscle (PMID:22081099) (PP4_Moderate). One Chinese patient with LOPD was compound heterozygous for the variant and a nonsense pathogenic variant c.2237G>A (p.Trp746*) at the same nucleotide; however, this patient has a third variant c.503G>A (p.Arg168Gln) with no phase information (PMID:24169249), so it's not used for PM3 point counting. Another Chinese patient was compound heterozygous for the variant (maternally inherited) and a pathogenic variant c.1935C>A (p.Asp645Glu) (paternally inherited) (PMID:33344388); and it's not used for PM3 point counting due to the complex phenotype and the lack other evidence supporting the diagnosis of LOPD. A third Chinese individual heterozygous for the variant, a pathogenic variant c.2662G>T (p.Glu888*), and a third variant c.2647-7G>A was detected by genome sequencing as newborn screening; and it's not used for PM3 point counting due to the lack of phenotype information. Six Italian patients (PMID:22081099) and one Spanish patient (PMID:34020684) with LOPD were heterozygous for the variant and c.-32-13T>G pathogenic variant with no phase information (1 point, max for homozygous patients) (PM3). Expression of the variant in COS or HEK293 cells resulted in 2% residual GAA activity in medium and 0.1% normal activity in cells and evidence of abnormal GAA synthesis and processing, leading to a Class B ("potentially less severe") classification (PMID:22644586). However, another in vitro study reported the variant as a "relatively mild mutation" but also class E "probably non-pathogenic" (PMID:23430493). Functional criteria is not applied due to inconsistent functional classification. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001733 (13/75034) in the African/African American population which is lower than the ClinGen Lysosomal Diseases Variant Curation Expert Panel (LD VCEP) threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.919 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A different missense variant c.2238G>C (p.Trp746Cys) on the same amino acid has been classified as pathogenic by the LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 188484; 2 star review status) with 7 submitters classifying the variant as pathogenic and 5 as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3, PM5, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP - Dec. 17, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA198797/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000678 AC: 17AN: 250744Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135734
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461216Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 726926
GnomAD4 genome 0.0000854 AC: 13AN: 152298Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74466
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:10
The p.Trp746Ser variant in GAA has been reported at least 3 individuals with glycogen storage disorder type II (GSD type II), two of whom were compound heterozygous with the variant a pathogenic variant on the other allele and also carried another variant (p.Gln743Arg) in cis (on the same allele as this variant) (Kroos 2008 PMID: 18425781, Liu 2013 PMID: 24169249, Preisler 2017 PMID: 28490439). It has also been identified in 0.03% (5/15284) of Latino/Admixed American chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 188484). In vitro functional studies suggest the variant impairs protein function (Kroos 2012 PMID: 22644586, Niño 2013 PMID: 23430493). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Several variants involving this codon (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) have been identified in individuals with GSD type II and have been classified as pathogenic in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive glycogen storage disorder type II. ACMG/AMP criteria applied: PM5_Strong, PM2_Supporting, PP3. -
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The NM_000152.5:c.2237G>C variant in GAA is a missense variant predicted to result in the substitution of tryptophan by serine at amino acid 746 (p.Trp746Ser). This variant has been reported in at least 11 patients with late onset Pompe disease (LOPD) (PMID: 18425781, 22081099, 24169249, 28490439, 33344388, 34020684), with two having GAA enzyme activity <10% in muscle (PMID: 22081099) (PP4_Moderate). One Chinese patient with LOPD was compound heterozygous for the variant and a nonsense pathogenic variant c.2237G>A (p.Trp746*) at the same nucleotide; however, this patient has a third variant c.503G>A (p.Arg168Gln) with no phase information (PMID: 24169249), so it's not used for PM3 point counting. Another Chinese patient was compound heterozygous for the variant (maternally inherited) and a pathogenic variant c.1935C>A (p.Asp645Glu) (paternally inherited) (PMID: 33344388); and it's not used for PM3 point counting due to the complex phenotype and the lack other evidence supporting the diagnosis of LOPD. A third Chinese individual heterozygous for the variant, a pathogenic variant c.2662G>T (p.Glu888*), and a third variant c.2647-7G>A was detected by genome sequencing as newborn screening; and it's not used for PM3 point counting due to the lack of phenotype information. Six Italian patients (PMID: 22081099) and one Spanish patient (PMID: 34020684) with LOPD were heterozygous for the variant and c.-32-13T>G pathogenic variant with no phase information (1 point, max for homozygous patients) (PM3). Expression of the variant in COS or HEK293 cells resulted in 2% residual GAA activity in medium and 0.1% normal activity in cells and evidence of abnormal GAA synthesis and processing, leading to a Class B ("potentially less severe") classification (PMID: 22644586). However, another in vitro study reported the variant as a "relatively mild mutation" but also class E "probably non-pathogenic" (PMID: 23430493). Functional criteria is not applied due to inconsistent functional classification. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001733 (13/75034) in the African/African American population which is lower than the ClinGen Lysosomal Diseases Variant Curation Expert Panel (LD VCEP) threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.919 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A different missense variant c.2238G>C (p.Trp746Cys) on the same amino acid has been classified as pathogenic by the LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 188484; 2 star review status) with 7 submitters classifying the variant as pathogenic and 5 as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3, PM5, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP - Dec. 17, 2024). -
The p.Trp746Ser variant in GAA has been reported in 1 Danish, 1 Chinese, 1 Northern European, and 6 Italian individuals with Glycogen Storage Disease II (PMID: 28490439, 24169249, 18425781, 22081099), and has been identified in 0.032% (8/24924) of African chromosomes and 0.011% (4/35424) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). 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 pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and Shahid Beheshti University of Medical Sciences in ClinVar (Variation ID: 188484). In vitro functional studies provide some evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). 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. The presence of this variant in combination with a reported pathogenic variant in 6 individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ser variant is pathogenic (PMID: 22081099). The phenotype of 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in muscle tissue, consistent with disease (PMID: 22081099). Four additional variants (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) at the the same position, including a reported pathogenic variant, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 265160, 556431, 499293, 284776). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II and functional evidence. ACMG/AMP Criteria applied: PS3, PM5, PM3_supporting, PM2, PP3, PP4 (Richards 2015). -
This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 746 of the GAA protein (p.Trp746Ser). This variant is present in population databases (rs752921215, gnomAD 0.03%). This missense change has been observed in individuals with Pompe disease (PMID: 18425781, 22081099). ClinVar contains an entry for this variant (Variation ID: 188484). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 23430493). This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18458862, 21232767, 21757382, 23430493, 25093132, 25526786, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: GAA c.2237G>C (p.Trp746Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250744 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (6.8e-05 vs 0.0042), allowing no conclusion about variant significance. c.2237G>C has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Angelini_2012). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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The classification of the variant was performed according to the recommendations of ClinGen lysosomal storage disorders variant curation expert panel (Guidelines version 2, specific for the GAA gene). The NM_000152.5:c.2237G>C p.(Trp746Ser) is a missense variant that replaces a highly conserved Trp with Ser. This variant is present at a very low frequency in gnomAD databases (ƒExomes = 0.0000678, ƒgenomes = 0.0000854), only in heterozygosity and meets the PM2_Supporting criterion (1pt). This variant is located in a mutational hot-spot sequence of 17 amino-acids length with 20 missense/in-frame variants (8 pathogenic variants, 12 uncertain variants) and without benign variation, which qualifies the c.2237G>C variant as moderate pathogenic (PM1 criterion, 2pts). Five pathogenic alternative variants [Trp746Cys (chr17:78090815G>T and chr17:78090815 G>C), Trp746Leu, Trp746Gly and Trp746Arg] affecting the same amino acid (Trp746) have been reported in association with disease in ClinVar (PM5_strong: 4pts). Multiple lines of computational evidence strongly support the pathogenicity of this variant (REVEL score: 0.919) and therefore meets the PP3 criterion (supporting, 1pt). The c.2237G>C variant confirmed to be in trans with different pathogenic or likely pathogenic variants (PMID: 25526786, PMID: 18429042, PMID: 12923862, PMID: 21484825, PMID: 16917947, PMID: 18285536) in individuals with Pompe disease, thus meets the PM3_very strong criterion (4pts). In vitro functional studies provide evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). In our study, the four individuals (with c.[266G>A];[2237G>C] genotype, 2-13 years) were found to have GAA activity clearly within the patient range (1.1-4.9nmol/h/mg) in leukocytes using 4-methylumbelliferyl-α-D-glucoside as a substrate. Using glycogen as a substrate, the GAA activity was found to be within the range for LOPD patients (3-10nmol/h/mg) for one subject and slightly above the upper limit for the three subjects. The presence of the KM-mutant polymorphism c.271G>A and the pseudodeficiency variant c.[1726G>A (p.Gly576Ser); 2065G>A (p.Glu689Lys)] was excluded. Based on the ClinGen LSD VCEP's specifications, this data meets PP4_Moderate rule (2pts). In summary, this variant meets the criteria to be classified as a pathogenic variant (total 14 pts) for Pompe disease. -
not provided Pathogenic:3
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Published functional studies demonstrate that p.(W746S) results in a significant reduction in enzymatic activity (Kroos et al., 2012; Nino et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24444888, 24169249, 18425781, 22644586, 23430493, 29325298, 30275481, 19343043, 22253258, 31589614, 27535533, 34906458, 26582918, 34020684, 33717985, 22081099, Jian2021, 33344388) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at