Submissions for variant NM_000152.5(GAA):c.716del (p.Leu239fs)

dbSNP: rs1555599594

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000672913	SCV001443323	pathogenic	Glycogen storage disease, type II	2020-09-20	reviewed by expert panel	curation	This variant, c.716delT (p.Leu239ArgfsTer29), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. One patient with this variant meets the ClinGen LSD VCEP's specifications for PP4. This patient is compound heterozygous for the variant and c.1447G>A (p.Gly483Arg) (PMID 31606152, personal communication). This in trans data will be used in the assessment of p.Gly483Arg and is not included here in order to avoid circular logic. Another patient who is compound heterozygous for the variant has been reported (PMID 14695532). However, residual GAA activity was not provided and this data was not included. Therefore, PM3 is not currently met. This variant is not in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 556853, 2 star review status) with one submitter classifying the variant as pathogenic and two 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, PM2, PP4.
Counsyl	RCV000672913	SCV000798068	likely pathogenic	Glycogen storage disease, type II	2018-02-21	criteria provided, single submitter	clinical testing
Hadassah Hebrew University Medical Center	RCV000672913	SCV001142800	likely pathogenic	Glycogen storage disease, type II	2019-06-20	criteria provided, single submitter	clinical testing
Invitae	RCV000672913	SCV001418830	pathogenic	Glycogen storage disease, type II	2021-12-17	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: 556853). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type II (PMID: 14695532). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu239Argfs*29) 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).
Revvity Omics, Revvity	RCV003140072	SCV003822640	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV003140072	SCV004022963	pathogenic	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in individuals with glycogen storage disease 2 (Hermans et al., 2004; Gupta et al., 2020); This variant is associated with the following publications: (PMID: 31254424, 31342611, 31606152, 14695532)