ClinVar Miner

Submissions for variant NM_022787.4(NMNAT1):c.293T>G (p.Val98Gly)

gnomAD frequency: 0.00011  dbSNP: rs771336246
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001074108 SCV001239677 pathogenic Retinal dystrophy 2019-01-05 criteria provided, single submitter clinical testing
GeneDx RCV001551709 SCV001772275 likely pathogenic not provided 2023-10-14 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant leads to reduced protein stability and enzymatic activity (Sasaki et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22842231, 26018082, 22842230, 22842227, 27535533, 32865313)
Labcorp Genetics (formerly Invitae), Labcorp RCV001256659 SCV002119164 pathogenic Leber congenital amaurosis 9 2024-11-19 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 98 of the NMNAT1 protein (p.Val98Gly). This variant is present in population databases (rs771336246, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of NMNAT1-related conditions (PMID: 22842227, 22842231; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 866255). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NMNAT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NMNAT1 function (PMID: 26018082). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV002221606 SCV002499105 likely pathogenic Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis 2022-03-09 criteria provided, single submitter clinical testing PS3, PM2, PM3, PP3
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001256659 SCV001433035 likely pathogenic Leber congenital amaurosis 9 no assertion criteria provided research

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