ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.953T>C (p.Met318Thr) (rs121907936)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727662 SCV000854969 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780268 SCV000917391 likely pathogenic Glycogen storage disease, type II 2018-03-09 criteria provided, single submitter clinical testing Variant summary: GAA c.953T>C (p.Met318Thr) results in a non-conservative amino acid change located in the N-terminal of the Glycoside hydrolase family 31 domain (IPR025887) of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 263770 control chromosomes (gnomAD and literature). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.9e-05 vs 4.20e-03), allowing no conclusion about variant significance. c.953T>C has been reported in the literature individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), (Zhong_1991, Mori_2017, Loscher_2018). At least one publication reports experimental evidence evaluating an impact on enzyme activity (Zhong_1991). The most pronounced variant effect resulted in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780268 SCV001199377 pathogenic Glycogen storage disease, type II 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 318 of the GAA protein (p.Met318Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs121907936, ExAC 0.02%). This variant has been observed in several individuals affected with Pompe disease (PMID: 1652892, 29181627, 19862843, 29122469). ClinVar contains an entry for this variant (Variation ID: 4021). This variant has been reported to affect GAA protein function (PMID: 19862843, 1652892). This variant disrupts the p.Met318 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21484825), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004236 SCV000024402 pathogenic Glycogen storage disease type II, infantile 1991-09-01 no assertion criteria provided literature only
Molecular Therapies Laboratory,Murdoch University RCV000780268 SCV001244231 pathogenic Glycogen storage disease, type II 2019-01-07 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000780268 SCV001423074 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Met318Thr variant in GAA has been reported in 2 individuals with Glycogen Storage Disease II (PMID: 1652892, 25139343), and has also been reported pathogenic by OMIM, likely pathogenic by Integrated Genetics, and a VUS by EGL Genetic Diagnostics in ClinVar (Variation ID: 4021). This variant has been identified in 0.009% (2/23234) of African chromosomes and 0.006% (7/121686) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907936). 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 with a minigene assay provide some evidence that the p.Met318Thr variant may eliminate GAA activity (PMID: 1652892). 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. However, the Methionine (Met) at position 318 is not conserved in evolutionary distant species, raising the possibility that a change at this position may be tolerated. Two additional variants at the same position, p.Met318Lys and p.Met318Leu, have been reported as VUS in ClinVar but p.Met318Lys is a likely pathogenic variant, slightly increasing the likelihood that the p.Met318Thr variant is pathogenic (Variation ID: 558700, 290616; PMID: 21484825, 22644586). This variant has been reported in combination with a reported likely pathogenic variant and a variant reported to cause NMD, and in individuals with Glycogen Storage Disease II (PMID: 1652892, 25139343). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM5_Supporting, PP3, PP4 (Richards 2015).

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