Submissions for variant NM_000152.5(GAA):c.700A>G (p.Thr234Ala)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002740069	SCV003000356	likely pathogenic	Glycogen storage disease, type II	2023-06-28	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr234 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22644586, 22676651, 34852371). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1963482). This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (PMID: 33202836). This variant is present in population databases (rs766931184, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the GAA protein (p.Thr234Ala).
Revvity Omics, Revvity	RCV003146611	SCV003834091	uncertain significance	not provided	2019-08-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700814	SCV005203344	uncertain significance	not specified	2024-07-05	criteria provided, single submitter	clinical testing	Variant summary: GAA c.700A>G (p.Thr234Ala) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of 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 4e-06 in 250968 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.700A>G has been reported in the literature in a newbown screening case with suspected Late Onset Pompe Disease (Ficicioglu_2020). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33202836). ClinVar contains an entry for this variant (Variation ID: 1963482). Based on the evidence outlined above, the variant was classified as uncertain significance.