Submissions for variant NM_000152.5(GAA):c.1128_1129delinsC (p.Trp376fs)

dbSNP: rs786204646

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169433	SCV001371728	pathogenic	Glycogen storage disease, type II	2020-02-14	reviewed by expert panel	curation	This variant, c.1128_1129delGGinsC (p.Trp376Cysfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. Two individuals have been reported who meet the ClinGen LSD VCEP's specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). There is a ClinVar entry for this variant (Variation ID: 189041, 2 star review status) with 3 submitters classifying the variant and pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3, PM2, PP4.
Counsyl	RCV000169433	SCV000220846	likely pathogenic	Glycogen storage disease, type II	2014-10-28	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000725812	SCV000339553	pathogenic	not provided	2017-04-03	criteria provided, single submitter	clinical testing
Invitae	RCV000169433	SCV000961782	pathogenic	Glycogen storage disease, type II	2022-05-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp376Cysfs*16) 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). 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 premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 18425781, 18607768, 22252923, 22676651). ClinVar contains an entry for this variant (Variation ID: 497032). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000725812	SCV002023857	pathogenic	not provided	2023-01-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169433	SCV004197805	pathogenic	Glycogen storage disease, type II	2023-07-04	criteria provided, single submitter	clinical testing
Molecular Therapies Laboratory, Murdoch University	RCV000169433	SCV001244228	pathogenic	Glycogen storage disease, type II	2019-01-07	no assertion criteria provided	clinical testing