Submissions for variant NM_000152.5(GAA):c.1375G>C (p.Asp459His)

dbSNP: rs535644999

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597199	SCV000702313	uncertain significance	not provided	2016-10-10	criteria provided, single submitter	clinical testing
Invitae	RCV000698293	SCV000826950	pathogenic	Glycogen storage disease, type II	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 459 of the GAA protein (p.Asp459His). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 497673). 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 with a positive predictive value of 95%. This variant disrupts the p.Asp459 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18458862, 21484825, 21757382). 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.
Genome-Nilou Lab	RCV000698293	SCV002027267	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323624	SCV004030053	uncertain significance	not specified	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1375G>C (p.Asp459His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250268 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1375G>C has been reported in the literature in at least one compound heterozygous individual affected with Glycogen Storage Disease, Type 2 (Pompe Disease; e.g., Burton_2020) and one infant affected with dilated cardiomyopathy, however without strong evidence for causality (e.g., Langanecha_2023 (Abstract, No PMID)). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33073003). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; 3 submitters classified the variant as VUS, and one submitter classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000698293	SCV001455613	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing