ClinVar Miner

Submissions for variant NM_022787.4(NMNAT1):c.716T>C (p.Leu239Ser) (rs778606847)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538650 SCV000639244 pathogenic Leber congenital amaurosis 9 2017-08-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 239 of the NMNAT1 protein (p.Leu239Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs778606847, ExAC 0.003%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Leber congenital amaurosis (PMID:22842229). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Experimental studies have shown that this missense change affects the ability NMNAT1 protein to block axon degeneration, alters its ability to properly bind substrate nicotinamide mononucleotide (NMN), and causes instability in protein secondary structure (PMID: 26018082). For these reasons, this variant has been classified as Pathogenic.

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