Submissions for variant NM_000152.5(GAA):c.379_380del (p.Cys127fs)

dbSNP: rs1207988953

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000668069	SCV002032110	pathogenic	Glycogen storage disease, type II	2021-08-19	reviewed by expert panel	curation	NM_000152.5:c.379_380del (p.Cys127LeufsTer18) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 patients with Pompe disease and this variant have been reported that meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. Of these patients, the available data includes documentation of laboratory values showing GAA deficiency (PMIDs 18757064, 24245577, 24715333, 30049495, 33162552). Furthermore, one of these patients had documented features consistent with infantile onset Pompe disease (PMID 24715333, 33162552) and another was on enzyme replacement therapy (PMID 30049495)(PP4_Moderate). These patients are all compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.525delT (PMID 24715333, 33162552), “del exon 18” (PMID 9660056), and c.-32-13T>G (PMID 17573812, 17643989, 18757064, 24245577, 33458579; at least two patients). Total 2 points (PM3_Strong). Another patients is compound heterozygous for the variant and c.2104C>T (p.Arg702Cys); phase unconfirmed (PMID 30049495). The in trans data from this patient will be used in the assessment of p.Arg702Cys and was not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 552747, two star review status) with two submitters classifying the variant as pathogenic. 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 Specification Version 2.0): PVS1, PM3_Strong, PP4_Moderate, PM2_Supporting.
Counsyl	RCV000668069	SCV000792613	pathogenic	Glycogen storage disease, type II	2017-07-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731154	SCV000858932	pathogenic	not provided	2018-01-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000731154	SCV002023855	pathogenic	not provided	2020-11-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668069	SCV002212446	pathogenic	Glycogen storage disease, type II	2023-07-19	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: 552747). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 9660056). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys127Leufs*18) 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).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000668069	SCV003808041	pathogenic	Glycogen storage disease, type II	2022-09-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong
Baylor Genetics	RCV000668069	SCV005058731	pathogenic	Glycogen storage disease, type II	2024-03-14	criteria provided, single submitter	clinical testing