Submissions for variant NM_000152.5(GAA):c.1705dup (p.Tyr569fs)

dbSNP: rs2143883097

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV002260938	SCV002540650	pathogenic	Glycogen storage disease, type II	2022-06-03	reviewed by expert panel	curation	The NM_000152.5:c.1705dup (p.Tyr569LeufsTer67) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 14/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient, with infantile onset Pompe disease, has been reported with residual GAA activity <10%, CRIM-negative, and with clinical improvements on enzyme replacement therapy (PMID 23601496, 33972680) (PP4_Moderate). This patient is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, c.1396del (PMID 23601496, 33972680). The phase is unknown. 0.5 points (PM3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.