Submissions for variant NM_000152.5(GAA):c.1103G>A (p.Gly368Asp)

dbSNP: rs368244038

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001340781	SCV003852731	likely pathogenic	Glycogen storage disease, type II	2022-12-20	reviewed by expert panel	curation	The NM_000152.5(GAA):c.1103G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 368 (p.Gly368Asp). This variant has been detected in at least 3 individuals with Pompe disease and deficient enzyme testing. Of those individuals, 3 were compound heterozygous for the variant and the pathogenic variant c.-32-13T>G and 1 of those were confirmed in trans by parental/family testing (PMID: 36246652, 33202836, internal lab data). (PM3 and PP4_Moderate). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in HEK293 cells resulted in 2.8% wild type GAA activity – and evidence of abnormal GAA synthesis and processing, indicating that this variant may impact protein function (PMID: 36246652) (PS3_Supporting). The computational predictor REVEL gives a score of 0.647 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 1037598, 1 star review status) with 1 submitter classifying the variant as a VUS. 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): PM3, PP4_Moderate, PM2_Supporting, PS3_Supporting. (Classification approved by the ClinGen LSD VCEP, December 20, 2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001340781	SCV001534609	likely pathogenic	Glycogen storage disease, type II	2022-04-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 33202836; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1037598). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 368 of the GAA protein (p.Gly368Asp).
Revvity Omics, Revvity	RCV003145584	SCV003828486	uncertain significance	not provided	2021-10-28	criteria provided, single submitter	clinical testing
GeneDx	RCV003145584	SCV003936613	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (significantly reduced enzyme activity) (Goomber et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36246652, 33202836)