17-80112015-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3PP4_ModeratePM2_SupportingPS3_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1669A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 557 (p.Ile557Phe). Three probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant (PMIDs 23884227, 25612604, clinical laboratory data), two with documented deficiency of GAA activity (PMIDs 23884227, 25612604) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.1978C>T (p.Arg660Cys) (clinical laboratory data); the variants are confirmed in trans by parental testing. The other two patients are compound heterozygous for the variant and a variant classified as uncertain significance by the ClinGen LSD VCEP, either c.2132C>G (p.Thr711Arg) or c.1385T>C (p.Leu462Pro). The allelic data for these latter two patients will be used in the assessment of p.Thr711Arg or p.Leu462Pro and is not included here to avoid circular logic (PM3). Two additional patients have been reported who were identified by newborn screening and carry pseudodeficiency variants; one asymptomatic and compound heterozygous for the variant and p.Thr711Arg (PMID:20080426), and the other heterozygous for the variant and presumably unaffected (PMID 31076647). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 2.7% GAA activity in cells and 0.3% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.662 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants, c.1669A>G (p.Ile557Val) (ClinVar Variation ID: 856959) and c.1670T>G (p.Ile557Ser) (PMID:26474166), in the same codon have been reported in patients with Pompe disease. However, these variants have been classified as variants of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 558634; 1 star review status) with one submitter classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401368911/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 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461650Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727158
GnomAD4 genome
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 14, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 557 of the GAA protein (p.Ile557Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 23884227). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 558634). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Mar 01, 2022 | The NM_000152.5:c.1669A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 557 (p.Ile557Phe). Three probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant (PMIDs 23884227, 25612604, clinical laboratory data), two with documented deficiency of GAA activity (PMIDs 23884227, 25612604) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.1978C>T (p.Arg660Cys) (clinical laboratory data); the variants are confirmed in trans by parental testing. The other two patients are compound heterozygous for the variant and a variant classified as uncertain significance by the ClinGen LSD VCEP, either c.2132C>G (p.Thr711Arg) or c.1385T>C (p.Leu462Pro). The allelic data for these latter two patients will be used in the assessment of p.Thr711Arg or p.Leu462Pro and is not included here to avoid circular logic (PM3). Two additional patients have been reported who were identified by newborn screening and carry pseudodeficiency variants; one asymptomatic and compound heterozygous for the variant and p.Thr711Arg (PMID: 20080426), and the other heterozygous for the variant and presumably unaffected (PMID 31076647). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 2.7% GAA activity in cells and 0.3% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.662 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants, c.1669A>G (p.Ile557Val) (ClinVar Variation ID: 856959) and c.1670T>G (p.Ile557Ser) (PMID: 26474166), in the same codon have been reported in patients with Pompe disease. However, these variants have been classified as variants of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 558634; 1 star review status) with one submitter classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PM2_Supporting. (Approved by LSD VCEP on Feb 15, 2022). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at