ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1409A>C (p.Asn470Thr)

gnomAD frequency: 0.00005  dbSNP: rs144155165
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000631067 SCV004227914 uncertain significance Glycogen storage disease, type II 2023-12-19 reviewed by expert panel curation The NM_000152.5:c.1409A>C variant in GAA is a missense variant predicted to cause substitution of Asn by Thr at amino acid 470 (p.Asn470Thr). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0001068 (8/74918 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.468 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It has been reported in two cases identified as affected by newborn screening (PMID 23430949, 37087815). There is insufficient data to apply PP4. There is a ClinVar entry for this variant (Variation ID: 526525, 2 star review status) with 3 submitters classifying the variant as Uncertain significance. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023).
Invitae RCV000631067 SCV000752058 uncertain significance Glycogen storage disease, type II 2022-09-01 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 470 of the GAA protein (p.Asn470Thr). 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 Pompe disease (PMID: 23430949). ClinVar contains an entry for this variant (Variation ID: 526525). 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 not expected to disrupt GAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV000631067 SCV002792584 uncertain significance Glycogen storage disease, type II 2021-09-13 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003129950 SCV003816194 uncertain significance not provided 2023-10-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV000631067 SCV004195469 likely pathogenic Glycogen storage disease, type II 2023-12-20 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.