Submissions for variant NM_000152.5(GAA):c.2185del (p.Leu729fs)

dbSNP: rs1057516581

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000412465	SCV002032108	pathogenic	Glycogen storage disease, type II	2021-11-19	reviewed by expert panel	curation	The NM_000152.5:c.2185del (p.Leu729TrpfsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in three individuals with infantile onset Pompe disease (PMIDs 19588081, 24269976, 28394184)(PP4). One of these individuals is homozygous for the variant (PMID 19588081)(PM3_Supporting); another individual is heterozygous for the variant but a second variant was not found (PMID, 24269976), and one is compound heterozygous for the variant and c.1935C>A (p.Asp645Glu)(PMID 28394184). The allelic data for this latter patient was used in the assessment of p.Asp645Glu and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variant ID 370552; 2 star review status) with one submitter classifying the variant as 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 met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting, PM3_Supporting.
Counsyl	RCV000412465	SCV000485900	likely pathogenic	Glycogen storage disease, type II	2016-02-26	criteria provided, single submitter	clinical testing
Invitae	RCV000412465	SCV000937166	pathogenic	Glycogen storage disease, type II	2022-01-16	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu729Trpfs*35) 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). This premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 19588081, 28394184). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370552).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412465	SCV002572217	pathogenic	Glycogen storage disease, type II	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2185delC (p.Leu729TrpfsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 199474 control chromosomes (gnomAD). c.2185delC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Oba-Shinjo_2009, Fu_2013, Nio_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1), including ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000412465	SCV004197866	pathogenic	Glycogen storage disease, type II	2023-02-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000412465	SCV002092111	pathogenic	Glycogen storage disease, type II	2021-08-16	no assertion criteria provided	clinical testing