Submissions for variant NM_000152.5(GAA):c.1841C>A (p.Thr614Lys)

dbSNP: rs369531647

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000591376	SCV001371751	pathogenic	Glycogen storage disease, type II	2020-04-21	reviewed by expert panel	curation	This variant, c.1841C>A (p.Thr614Lys), has been found in two patients published in the literature and five patients in a clinical diagnostic laboratory who have Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. These patients are compound heterozygous for the variant and either c.1076–22T>G (PMID 21484825), c.-32-13T>G (PMID 24590251, 2 laboratory patients), c.2481+102_2646+31del (one patient), c.1402A>T (p.Ile468Phe) (one patient), and unconfirmed second variant (one patient). The phase of the variants is unknown for all patients. This in trans data meets PM3. Pseudodeficiency variants are absent in the patients identified in the clinical laboratory. Therefore, PP4_Moderate can be applied. When expressed in COS cells, this variant resulted in <5% wild type activity in cells and <2% wild type activity in medium, in addition to exhibiting abnormal synthesis and processing (PMID 22644586), meeting PS3. The score for the REVEL in silico predictor, 0.835, also suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 167113, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3, PP3, PP4_Moderate.
Eurofins Ntd Llc (ga)	RCV000723464	SCV000700459	pathogenic	not provided	2018-02-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000591376	SCV000823521	pathogenic	Glycogen storage disease, type II	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 614 of the GAA protein (p.Thr614Lys). This variant is present in population databases (rs369531647, gnomAD 0.005%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21484825, 24590251, 27708273; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167113). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000591376	SCV001362500	pathogenic	Glycogen storage disease, type II	2019-09-07	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1841C>A (p.Thr614Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 244678 control chromosomes. c.1841C>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Kroos_2008, Kroos_2012, Bali_2011, Beltran-Papsdorf_2014, Reddy_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000591376	SCV001422904	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Thr614Lys variant in GAA has been reported in at least 5 individuals with Glycogen Storage Disease II (PMID: 21484825, 18425781, 24590251, 27708273) and has also been reported pathogenic by EGL Genetic Diagnostics and likely pathogenic by Invitae and Counsyl in ClinVar (Variation ID: 167113). This variant has been identified in 0.005% (6/125426) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs369531647). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Thr614Lys variant may impact GAA activity and protein levels (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Thr614Lys variant is pathogenic (PMID: 21484825, 24590251). The phenotype of 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues (PMID: 21484825, 24590251). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PS3, PM3, PM2, PP3, PP4 (Richards 2015).
GeneDx	RCV000723464	SCV001759142	pathogenic	not provided	2020-07-22	criteria provided, single submitter	clinical testing	Functional studies of T614K expressed protein demonstrate reduced enzyme activity and reduced synthesis or processing of alpha-glucosidase (Kroos et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31086307, 24590251, 23891399, 27708273, 25544546, 21484825, 18425781, 22644586)
Revvity Omics, Revvity	RCV000723464	SCV002023864	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000723464	SCV002502031	pathogenic	not provided	2022-02-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000591376	SCV002813681	pathogenic	Glycogen storage disease, type II	2021-10-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000591376	SCV004195422	pathogenic	Glycogen storage disease, type II	2024-03-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000591376	SCV004565259	pathogenic	Glycogen storage disease, type II	2023-03-31	criteria provided, single submitter	clinical testing	The GAA c.1841C>A; p.Thr614Lys variant (rs369531647) is reported in the literature in the compound heterozygous state in several individuals affected with Pompe disease (Bali 2011, Beltran Papsdorf 2014, Kroos 2008). This variant is also reported in ClinVar (Variation ID: 167113), and is found in the general population with an overall allele frequency of 0.0022% (6/276042 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.835). In vitro functional analyses demonstrate reduced protein levels and enzyme activity (Kroos 2012). Based on available information, this variant is considered to be pathogenic. References: Bali DS et al. Molecular analysis and protein processing in late-onset Pompe disease patients with low levels of acid alpha-glucosidase activity. Muscle Nerve. 2011 May;43(5):665-70. PMID: 21484825. Beltran Papsdorf TB et al. Pearls & Oy-sters: clues to the diagnosis of adult-onset acid maltase deficiency. Neurology. 2014 Mar 4;82(9):e73-5. PMID: 24590251. 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. PMID: 18425781. Kroos M et al. Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. Hum Mutat. 2012 Aug;33(8):1161-5. PMID: 22644586.
Mayo Clinic Laboratories, Mayo Clinic	RCV000723464	SCV005413277	pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	PP3, PP4_moderate, PM2, PM3, PS3
Counsyl	RCV000591376	SCV000791287	likely pathogenic	Glycogen storage disease, type II	2019-03-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000591376	SCV001459738	likely pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing