ClinVar Miner

Submissions for variant NM_018297.4(NGLY1):c.1025A>G (p.Tyr342Cys)

gnomAD frequency: 0.00002  dbSNP: rs757712371
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV002468613 SCV001149852 pathogenic Congenital disorder of deglycosylation 1 2020-12-09 criteria provided, single submitter clinical testing
Invitae RCV000995587 SCV002123910 pathogenic Congenital disorder of deglycosylation 2023-12-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 342 of the NGLY1 protein (p.Tyr342Cys). This variant is present in population databases (rs757712371, gnomAD 0.003%). This missense change has been observed in individual(s) with NGLY1-related conditions (PMID: 31965062). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 807450). 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 NGLY1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NGLY1 function (PMID: 31965062). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003148909 SCV003837210 pathogenic not provided 2022-09-12 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, as the Y342C enzyme failed to cleave an oligosaccharide substrate, resulting in no glycosidase activity (Abuduxikuer et al., 2020); 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: 35565658, 33497766, 31965062, 35406718, 32422350, 33098801, 33619735)

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