Submissions for variant NM_000027.4(AGA):c.755G>A (p.Gly252Glu)

dbSNP: rs386833433

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001509243	SCV001715848	likely pathogenic	not provided	2019-05-21	criteria provided, single submitter	clinical testing	PS3, PM2, PM3, PP4
Invitae	RCV000049361	SCV002254402	uncertain significance	Aspartylglucosaminuria	2022-03-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 252 of the AGA protein (p.Gly252Glu). This variant is present in population databases (rs386833433, gnomAD 0.003%). This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 11309371). ClinVar contains an entry for this variant (Variation ID: 55952). 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 AGA protein function. Experimental studies have shown that this missense change affects AGA function (PMID: 11309371). This variant disrupts the p.Gly252 amino acid residue in AGA. Other variant(s) that disrupt this residue have been observed in individuals with AGA-related conditions (PMID: 11309371), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222374	SCV002500066	uncertain significance	not specified	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: AGA c.755G>A (p.Gly252Glu) 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 4e-06 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.755G>A has been reported in the literature as a compound heterozygous genotype in at-least one Finnish individual affected with Aspartylglucosaminuria (example, Saarela_2001). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic citing overlapping clinical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001509243	SCV003798657	likely pathogenic	not provided	2022-07-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that p.(G252E) likely causes protein misfolding resulting in an inactivate precursory polypeptide that remains in the endoplasmic reticulum and is unprocessed (Saarela et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32415113, 11754099, 11309371, 18992224)
Baylor Genetics	RCV000049361	SCV004217750	likely pathogenic	Aspartylglucosaminuria	2023-05-17	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049361	SCV000081793	probable-pathogenic	Aspartylglucosaminuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.