ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1385T>C (p.Leu462Pro)

dbSNP: rs2143866454
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV002260941 SCV002540659 uncertain significance Glycogen storage disease, type II 2022-05-11 reviewed by expert panel curation The NM_000152.5:c.1385T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 462 (p.Leu462Pro). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The variant has been reported in an 8 month old male with clinical features consistent with infantile onset Pompe disease and documentation of deficient GAA activity (PMID 25612604) (PP4_Moderate). This patient is compound heterozygous for the variant and another missense variant that has been classified as a variant of uncertain significance by the ClinGen LSD VCEP (PMID 25612604). To our knowledge, the results of functional assays are not available for this variant. The computational predictor REVEL gives a score of 0.951 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PP3, PM2_Supporting.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV002260941 SCV005043134 pathogenic Glycogen storage disease, type II 2024-04-06 criteria provided, single submitter clinical testing A heterozygous variant in exon 9 of the GAA gene that results in the amino acid substitution of Proline for Leucine at codon 462 was detected. The observed variant c.1385T>C has not been reported in the 1000 genomes and gnomAD database. The in-silico prediction of the variant is damaging by MutationTaster and DANN. In summary, the variant meets our criteria to be classified as pathogenic.

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