Submissions for variant NM_000152.5(GAA):c.1841C>T (p.Thr614Met)

dbSNP: rs369531647

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000702676	SCV002583369	likely pathogenic	Glycogen storage disease, type II	2022-09-19	reviewed by expert panel	curation	The NM_000152.5:c.1841C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 614 (p.Thr614Met). At least 2 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PP4_Moderate). This variant has been detected in at least 3 individuals with Pompe disease. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic variant (PMID: 33741225). At least 2 individuals were homozygous for the variant (PMID: 33301762, 33741225, 33250842) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004184 (1/23902 alleles) in the African/African-American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.769 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5). Splicing prediction using Splice AI revealed no expected effects on splicing due to either of these variants. There is a ClinVar entry for this variant (Variation ID: 286469, 1 star review status) with 3 submitters classifying the variant as uncertain significance, 2 submitters as likely pathogenic, and 1 submitter as pathogenic. 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): PP4_Moderate, PP3, PM3, PM5, PM2_Supporting
Eurofins Ntd Llc (ga)	RCV000295145	SCV000339910	uncertain significance	not provided	2016-02-25	criteria provided, single submitter	clinical testing
Invitae	RCV000702676	SCV000831539	pathogenic	Glycogen storage disease, type II	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 614 of the GAA protein (p.Thr614Met). This variant is present in population databases (rs369531647, gnomAD 0.003%). This missense change has been observed in individuals with late onset Pompe disease (PMID: 33250842, 33741225). ClinVar contains an entry for this variant (Variation ID: 286469). 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.Thr614 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21484825, 24513544, 24590251, 27708273). 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.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000702676	SCV001438059	pathogenic	Glycogen storage disease, type II	2020-10-15	criteria provided, single submitter	clinical testing	The variant c.1841C>T has been reported by Nallamilli et. al. 2018 PMID:30564623
Mayo Clinic Laboratories, Mayo Clinic	RCV000295145	SCV001713741	uncertain significance	not provided	2019-10-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000295145	SCV001802214	likely pathogenic	not provided	2020-11-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33250842)
Genome-Nilou Lab	RCV000702676	SCV001810629	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000702676	SCV002051326	likely pathogenic	Glycogen storage disease, type II	2021-12-23	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1841C>T (p.Thr614Met) 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 8.2e-06 in 244678 control chromosomes. c.1841C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, Chakravorty_2020, Puri_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Puri_2021). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=3, VUS n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000295145	SCV003828492	uncertain significance	not provided	2022-01-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000702676	SCV004195461	likely pathogenic	Glycogen storage disease, type II	2023-10-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000702676	SCV004564453	likely pathogenic	Glycogen storage disease, type II	2023-03-09	criteria provided, single submitter	clinical testing	The GAA c.1841C>T; p.Thr614Met variant (rs369531647) is reported in the literature in multiple individuals affected with Pompe disease, one individual carried a second GAA variant, and several individuals were homozygous for p.Thr614Met (Chakravorty 2020, Puri 2021, Thomas 2021). This variant is also reported in ClinVar (Variation ID: 286469). This variant is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.1841C>A, p.Thr614Lys) have been reported in individuals with Pompe disease and are considered pathogenic (Kroos 2008, Reddy 2017). Computational analyses predict that this variant is deleterious (REVEL: 0.769). Based on available information, this variant is considered to be likely pathogenic. References: Chakravorty S et al. Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. Front Neurol. 2020 Nov 5;11:559327. PMID: 33250842. Kroos M et al. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745. PMID: 18425781. Puri RD et al. Late onset Pompe Disease in India - Beyond the Caucasian phenotype. Neuromuscul Disord. 2021 May;31(5):431-441. PMID: 33741225. Reddy HM et al. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet. 2017 Feb;62(2):243-252. PMID: 27708273. Thomas DC et al. Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease. Clin Biochem. 2021 Mar;89:14-37. PMID: 33301762.