rs1555600061
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PM2_SupportingPM3_StrongPS3_SupportingPP4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.1099T>C (p.Trp367Arg) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.0000013 (1/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant has been reported in at least 3 patients with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and/or on enzyme replacement therapy (ERT) (PMID:17056254‚ 22658377, 23787031, 25139343, 31510962); it was also reported in one patient of late-onset Pompe disease (LOPD) (PMID:22958975) (PP4_Moderate). This variant was found to be homozygous in one Spanish-Italian patient with IOPD and was confirmed to be inherited from both parents (PMID:17056254). At least one Hispanic patient with IOPD under ERT (PMID:22658377, 23787031, 25139343) was found to be compound heterozygous (phase unknown) for this variant and c.1802C>T (p.Ser601Leu), a GAA variant classified as pathogenic by the ClinGen LD VCEP. This variant was confirmed to be in trans with c.1942G>A (p.Gly648Ser), a GAA variant classified as pathogenic by the ClinGen LD VCEP, in a Thailand patient with IOPD (PMID:31510962). One Italian patient with LOPD was reported to be compound heterozygous (phase unknown) for the variant and c.-32-13T>G, the most common pathogenic GAA variant associated with LOPD (PMID:22958975) (PM3_Strong). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity without mature processed GAA protein on immunoblots, indicating a negative impact on GAA function (PMID:19862843) (PS3_Supporting). The computational meta-predictor REVEL has a score of 0.944 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). Another missense variant, c.1099T>G (p.Trp367Gly), in the same codon has been reported in a patient with LOPD (PMID:29124014). However, the data for p.Trp367Arg will be used in the assessment of p.Trp367Gly and therefore PM5 is not met here in order to avoid circular argument. There is a ClinVar entry for this variant (Variation ID: 555820). 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_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen LD VCEP, on December 5, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401364951/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 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1099T>C | p.Trp367Arg | missense_variant | 7/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1099T>C | p.Trp367Arg | missense_variant | 7/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460828Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0AN XY: 726736
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:5Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 10, 2018 | Variant summary: GAA c.1099T>C (p.Trp367Arg) 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 was absent in 244902 control chromosomes (gnomAD). c.1099T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), including a homozygous patient (Palmer 2007, Palermo 2012, Musumeci 2012, Mori 2017). These data indicate that the variant is likely to be associated with disease. One of these publications also reported that GAA enzyme activity levels measured from a dried blood spot were outside the range of normal activity in a homozygous patient (Palmer 2007). At least one other publication reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <2% of normal activity (Flanagan 2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Dec 05, 2023 | The NM_000152.5: c.1099T>C (p.Trp367Arg) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.0000013 (1/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant has been reported in at least 3 patients with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and/or on enzyme replacement therapy (ERT) (PMID: 17056254‚ 22658377, 23787031, 25139343, 31510962); it was also reported in one patient of late-onset Pompe disease (LOPD) (PMID: 22958975) (PP4_Moderate). This variant was found to be homozygous in one Spanish-Italian patient with IOPD and was confirmed to be inherited from both parents (PMID: 17056254). At least one Hispanic patient with IOPD under ERT (PMID: 22658377, 23787031, 25139343) was found to be compound heterozygous (phase unknown) for this variant and c.1802C>T (p.Ser601Leu), a GAA variant classified as pathogenic by the ClinGen LD VCEP. This variant was confirmed to be in trans with c.1942G>A (p.Gly648Ser), a GAA variant classified as pathogenic by the ClinGen LD VCEP, in a Thailand patient with IOPD (PMID: 31510962). One Italian patient with LOPD was reported to be compound heterozygous (phase unknown) for the variant and c.-32-13T>G, the most common pathogenic GAA variant associated with LOPD (PMID: 22958975) (PM3_Strong). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity without mature processed GAA protein on immunoblots, indicating a negative impact on GAA function (PMID: 19862843) (PS3_Supporting). The computational meta-predictor REVEL has a score of 0.944 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). Another missense variant, c.1099T>G (p.Trp367Gly), in the same codon has been reported in a patient with LOPD (PMID: 29124014). However, the data for p.Trp367Arg will be used in the assessment of p.Trp367Gly and therefore PM5 is not met here in order to avoid circular argument. There is a ClinVar entry for this variant (Variation ID: 555820). 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_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen LD VCEP, on December 5, 2023). - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Dec 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 367 of the GAA protein (p.Trp367Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 17056254, 22958975, 23787031, 31510962). 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: 555820). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 06, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at