ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.316C>T (p.Arg106Cys)

gnomAD frequency: 0.00001  dbSNP: rs915675670
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001247855 SCV004809075 uncertain significance Glycogen storage disease, type II 2024-02-06 reviewed by expert panel curation The NM_000152.5:c.316C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 106 (p.Arg106Cys). The variant has been detected in at least two individuals with suspected late-onset Pompe disease identified by newborn screening. One of those individuals was compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G (ClinVar Variation ID: 4027), confirmed in trans by parental testing (PMID: 36246652, 37670900); this patient reportedly had abnormalities on muscle ultrasound and mild gross motor delays (PM3). The genotype of another newborn screening case is unknown (PMID: 33073007). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/111012 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in HEK293 cells resulted in 10.7% GAA activity and the evidence of reduced protein relative to activity and normal processing on western blot, indicating that variant may impact protein function (PMID-36246652). The computational predictor REVEL gives a score of 0.567 which is 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.316C>G (p.Arg106Gly) (ClinVar variation ID: 840775 ) and c.317G>A (p.Arg106His) (PMID-31076647), in the same codon have been reported in patients identified by newborn screen. However, these variants have been classified as variants of uncertain significance by the ClinGen Lysosomal Diseases VCEP and, therefore this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 971945). In summary this variant meets the criteria to be classified as a variant of uncertain significance for Pome disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PM2_Supporting, PS3_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Feb 6, 2024).
Labcorp Genetics (formerly Invitae), Labcorp RCV001247855 SCV001421306 likely pathogenic Glycogen storage disease, type II 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 106 of the GAA protein (p.Arg106Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with late-onset Pompe disease (PMID: 35123877). 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: 971945). 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: 36246652). This variant disrupts the p.Arg106 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31076647). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity RCV003130231 SCV003810583 uncertain significance not provided 2023-10-26 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV003130231 SCV005408528 uncertain significance not provided 2024-08-22 criteria provided, single submitter clinical testing PM2, PM3, PS3_supporting
Natera, Inc. RCV001247855 SCV002091908 uncertain significance Glycogen storage disease, type II 2020-08-03 no assertion criteria provided clinical testing

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