rs61736895
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM3PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID:33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID:22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815746/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 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.2455C>T | p.Arg819Trp | missense_variant | 17/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.2455C>T | p.Arg819Trp | missense_variant | 17/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000247 AC: 6AN: 243096Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132380
GnomAD4 exome AF: 0.0000391 AC: 57AN: 1459040Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 725742
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74344
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:2Uncertain:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Dec 20, 2023 | The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID: 33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID: 22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 819 of the GAA protein (p.Arg819Trp). This variant is present in population databases (rs61736895, gnomAD 0.009%). This missense change has been observed in individual(s) with Pompe disease (PMID: 33741225). ClinVar contains an entry for this variant (Variation ID: 456402). 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%. This variant disrupts the p.Arg819 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 31, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); 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: 19343043, 22253258, 33741225) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2023 | Variant summary: GAA c.2455C>T (p.Arg819Trp) 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 2.5e-05 in 243096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2455C>T has been reported in the literature in an individual affected with Glycogen Storage Disease (example: Puri_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33741225). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the varinat as VUS (n=5) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2021 | The p.R819W variant (also known as c.2455C>T), located in coding exon 16 of the GAA gene, results from a C to T substitution at nucleotide position 2455. The arginine at codon 819 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. 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