Submissions for variant NM_000152.5(GAA):c.896T>G (p.Leu299Arg)

dbSNP: rs121907940

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000795023	SCV002540652	likely pathogenic	Glycogen storage disease, type II	2022-05-11	reviewed by expert panel	curation	The NM_000152.5:c.896T>G variant in GAA is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 299 (p.Leu299Arg). This variant has been detected in 1 individual with Pompe disease. This individual was compound heterozygous for the variant and a pathogenic variant, an exon 18 deletion previously assessed by the ClinGen LSD VCEP (PMID:7603531,7717400) (PM3_Supporting). The patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts, but exact values for the patient's GAA activity and laboratory control values for GAA activity were not provided and PP4 could not be applied (PMID:7717400). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity, indicating that this variant may impact protein function (PMID:19862843), meeting criteria for PS3_Supporting. Expression of the variant in TR4219 cells in a separate study resulted in "complete loss of GAA activity" (PMID:7717400). REVEL Score = 0.93 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 4025, 1 star review status) with 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PM5, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795023	SCV000934461	pathogenic	Glycogen storage disease, type II	2020-01-04	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Leu299Arg and p.Leu299Pro) in affected individuals suggests that this may be a clinically significant residue (PMID: 25752415, 7717400). This variant has been reported to affect GAA protein function (PMID: 7717400, 19862843). Additionally, advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. This variant has been observed in individuals affected with Pompe disease (PMID: 7717400, Invitae). ClinVar contains an entry for this variant (Variation ID: 4025). This sequence change replaces leucine with arginine at codon 299 of the GAA protein (p.Leu299Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine.
OMIM	RCV000004240	SCV000024406	pathogenic	Glycogen storage disease type II, infantile	1995-04-01	no assertion criteria provided	literature only