Submissions for variant NM_000152.5(GAA):c.1431del (p.Ile477fs)

dbSNP: rs1598580364

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000855787	SCV001443325	pathogenic	Glycogen storage disease, type II	2023-04-11	reviewed by expert panel	curation	The NM_000152.5:c.1431del (p.Ile477MetfsTer43) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient from Saudi Arabia, homozygous for the variant, has been reported with infantile onset Pompe disease, on enzyme replacement therapy (PMID: 27629047, 30023291) (PM3_Supporting, PP4). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 694453). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023)
Medical Molecular Genetics Department, National Research Center	RCV000855787	SCV000998900	pathogenic	Glycogen storage disease, type II	2019-07-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000855787	SCV004296870	pathogenic	Glycogen storage disease, type II	2023-03-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 694453). This premature translational stop signal has been observed in individual(s) with GAA-related conditions (PMID: 27629047). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile477Metfs*43) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000855787	SCV004806771	uncertain significance	Glycogen storage disease, type II	2024-03-26	criteria provided, single submitter	clinical testing