Submissions for variant NM_000152.5(GAA):c.1716C>G (p.His572Gln)

dbSNP: rs772962666

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001194239	SCV002540653	likely pathogenic	Glycogen storage disease, type II	2022-05-11	reviewed by expert panel	curation	The NM_000152.5(GAA):c.1716C>G variant in GAA is a missense variant predicted cause the substitution of histidine by clutamine at amino acid 572 (p.His572Gln). At least 3 patients with this variant had had documented GAA deficiency with activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot (PMID: 3112512) or were reported to be on enzyme replacement therapy for Pompe disease (PMIDs: 25455803, 29122469), meeting PP4_Moderate. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic variant, phase unknown. One patient was compound heterozygous for the variant and c.-32-13T>G ( PMID: 31125121). One patient was compound heterozygous for c.1716C>G (p.His572Gln) and c.1293_1312del20 (p.Gln433Aspfs*66) (PMID: 29122469), meeting the specifications for PM3. This variant is absent in gnomAD, meeting PM2_Supporting. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.793 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP (Specifications Verion 2.0): PP4_Moderate, PM3, PS3_Moderate, PM2_Supporting, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194239	SCV001363618	likely pathogenic	Glycogen storage disease, type II	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1716C>G (p.His572Gln) results in a non-conservative amino acid change located in the Catalytic GH31 domain (PMID 29061980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes (gnomAD). c.1716C>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Kroos_2008, Vill_2015, Mori_2017, Kishnani_2019, Thomas_2021, Enax-Krumova_2022), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in loss of acid alpha-glucosidase activity (Kroos_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18425781, 22644586, 29122469, 30442156, 25455803, 33301762, 31086307, 35477515). ClinVar contains an entry for this variant (Variation ID: 929167). Two submitters, including a ClinGen expert panel, classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV003145370	SCV003832440	likely pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing
Invitae	RCV001194239	SCV004296880	pathogenic	Glycogen storage disease, type II	2023-08-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His572 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31086307, 33301762). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 929167). This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 31086307, 33301762). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 572 of the GAA protein (p.His572Gln).