ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1841C>A (p.Thr614Lys) (rs369531647)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723464 SCV000700459 pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
Invitae RCV000591376 SCV000823521 pathogenic Glycogen storage disease, type II 2020-09-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 614 of the GAA protein (p.Thr614Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs369531647, ExAC 0.004%). This variant has been reported in several individuals, who carried a second variant in GAA, affected with Pompe disease (PMID: 24590251, 27708273, 21484825, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167113). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
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)
Counsyl RCV000591376 SCV000791287 likely pathogenic Glycogen storage disease, type II 2019-03-02 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000591376 SCV001422904 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided 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,; 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).
Natera, Inc. RCV000591376 SCV001459738 likely pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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