ClinVar Miner

Submissions for variant NM_000027.4(AGA):c.677G>A (p.Gly226Asp)

gnomAD frequency: 0.00003  dbSNP: rs386833431
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000300295 SCV000329847 pathogenic not provided 2022-09-26 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect of significantly reduced enzyme activity (Sui et al., 2014; Saarela et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18992224, 25525159, 10399108, 11309371, 14616088, 28457719, 25456816)
Invitae RCV000049359 SCV001378538 pathogenic Aspartylglucosaminuria 2023-11-09 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 226 of the AGA protein (p.Gly226Asp). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs386833431, gnomAD 0.002%). This missense change has been observed in individual(s) with AGA-related conditions (PMID: 10399108, 29930972). ClinVar contains an entry for this variant (Variation ID: 55950). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGA function (PMID: 11309371, 18992224). Studies have shown that this missense change results in skipping of exon 6 and introduces a new termination codon (PMID: 10399108, 11309371). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000049359 SCV002809740 likely pathogenic Aspartylglucosaminuria 2021-07-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV000049359 SCV004217516 pathogenic Aspartylglucosaminuria 2023-10-28 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049359 SCV000081791 probable-pathogenic Aspartylglucosaminuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000049359 SCV001132325 likely pathogenic Aspartylglucosaminuria 2019-01-22 no assertion criteria provided clinical testing

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