Submissions for variant NM_000152.5(GAA):c.1445C>T (p.Pro482Leu)

dbSNP: rs2039212985

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001261923	SCV003852730	likely pathogenic	Glycogen storage disease, type II	2023-02-07	reviewed by expert panel	curation	The NM_000152.5:c.1445C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 482 (p.Pro482Leu). At least 5 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot, or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 31086307, 34530085, 33741225, 31931849) (PP4_Moderate). Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (p.Asp404Asn, p.Asn87Glnfs*9) (PMID: 31086307, 31931849). One individual was homozygous for the variant (PMID: 33741225) (PM3). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.1445C>G (p.Pro482Arg) (PMID: 31392188, 22644586, ClinVar Variation ID 1067574) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 982297; 2 star review status) with two submitters 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): PP4_Moderate, PM3, PP3, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen LSD VCEP, February 7, 2023).
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV001261923	SCV001438057	pathogenic	Glycogen storage disease, type II	2020-10-15	criteria provided, single submitter	clinical testing	The variant c.1445C>T has been reported in Gort et. al. 2007 PMID: 17616415
Revvity Omics, Revvity	RCV001780211	SCV002025224	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001261923	SCV002060049	likely pathogenic	Glycogen storage disease, type II	2021-11-16	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.1445C>T(P482L) is a missense variant classified as likely pathogenic in the context of Pompe disease. P482L has been observed in cases with relevant disease (PMID: 31931849, 31086307, 17616415, 33741225, Cerón-Rodríguez_2014_(no PMID; article)). Functional assessments of this variant are not available in the literature. P482L has not been observed in population frequency databases. In summary, NM_000152.3(GAA):c.1445C>T(P482L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001261923	SCV002238325	pathogenic	Glycogen storage disease, type II	2022-09-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 982297). 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 disrupts the p.Pro482 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18425781, 29122469, 31392188; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with Pompe disease (PMID: 17616415, 31086307). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 482 of the GAA protein (p.Pro482Leu). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001261923	SCV005185110	pathogenic	Glycogen storage disease, type II	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1445C>T (p.Pro482Leu) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, TIM barrel domain (IPR000322) 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 250910 control chromosomes. c.1445C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in the homozygous or compound heterozygous state (Aminoso_2022, Bevilacqua_2020, Gort_2007, Kishnani_2019, Puri_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34530085, 31931849, 17616415, 31086307, 33741225). ClinVar contains an entry for this variant (Variation ID: 982297). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001261923	SCV005653206	likely pathogenic	Glycogen storage disease, type II	2024-05-23	criteria provided, single submitter	clinical testing