Submissions for variant NM_000152.5(GAA):c.883C>A (p.His295Asn)

dbSNP: rs751639773

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001226064	SCV005903296	likely pathogenic	Glycogen storage disease, type II	2024-12-19	reviewed by expert panel	curation	The NM_000152.5:c.883C>A variant in GAA is a missense variant predicted to cause substitution of His by Asn at amino acid 295 (p.His295Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (3/24448 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2 (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.716 which is above the thresholds predicting a damaging (>0.7) impact on GAA function (PP3. This variant has been detected in 1 individual with Pompe disease, who was compound heterozygous for the variant and variant c.2560C>T (VCEP Pathogenic) with unknown phase (PMID: 37087815). It has also been detected in 1 individual with low GAA enzyme activity with compound heterozygous for the variant and variant c.1962_1964delAGA; p.Glu655del (VCEP Pathogenic) with unknown phase (Clinical lab data), thus met PM3. At least 2 patient with this variant had documented GAA activity in blood (PMID: 37087815; clinical lab), meeting PP4_Moderate. There is a ClinVar entry for this variant (Variation ID: 953728). 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 Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_supporting, PP3, PM3, PP4_moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001226064	SCV001398360	uncertain significance	Glycogen storage disease, type II	2022-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 295 of the GAA protein (p.His295Asn). This variant is present in population databases (rs751639773, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 953728). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV001226064	SCV002777510	uncertain significance	Glycogen storage disease, type II	2021-09-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003145424	SCV003834061	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001226064	SCV002091976	uncertain significance	Glycogen storage disease, type II	2021-01-20	no assertion criteria provided	clinical testing