Submissions for variant NM_000152.5(GAA):c.1445C>G (p.Pro482Arg)

dbSNP: rs2039212985

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001378875	SCV003852728	likely pathogenic	Glycogen storage disease, type II	2022-12-06	reviewed by expert panel	curation	The NM_000152.5:c.1445C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 482 (p.Pro482Arg). One proband with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID: 31392188) (PP4). This proband is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.-32-13T>G (PM3_Supporting). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.948 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 1067574; 1 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 Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PS3_Moderate, PP3, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen LSD VCEP, December 6, 2022).
Invitae	RCV001378875	SCV001576562	pathogenic	Glycogen storage disease, type II	2023-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro482 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 17616415), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). 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. ClinVar contains an entry for this variant (Variation ID: 1067574). This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 29122469, 31392188; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the GAA protein (p.Pro482Arg).
Revvity Omics, Revvity	RCV001780289	SCV002025212	likely pathogenic	not provided	2020-06-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001378875	SCV002775819	likely pathogenic	Glycogen storage disease, type II	2021-10-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001378875	SCV004197833	likely pathogenic	Glycogen storage disease, type II	2023-05-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001378875	SCV002092036	likely pathogenic	Glycogen storage disease, type II	2021-10-13	no assertion criteria provided	clinical testing