ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 237 of the NMNAT1 protein (p.Arg237Cys). This variant is present in population databases (rs375110174, gnomAD 0.02%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 22842227, 22842229, 26316326). 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: 845745). 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 NMNAT1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NMNAT1 function (PMID: 22842227, 26018082). For these reasons, this variant has been classified as Pathogenic.

The NMNAT1 c.709C>T (p.Arg237Cys) variant has been observed in individual(s) with Leber congenital amaurosis in compound heterozygous as well as homozygous state(Falk MJ et al). This variant is reported with the allele frequency (0.0049%) in the gnomad and novel (not in any individuals) in 1000 genome database. It has been submitted to ClinVar Pathogenic. The amino acid Arg at position 237 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg237Cys in NMNAT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, molecular diagnosis can not be confirmed.

The NMNAT1 c.709C>T (p.Arg237Cys) variant has been reported in the compound heterozygous state with a pathogenic variant in at least six unrelated individuals affected with leber congenital amaurosis (Coppieters F et al., PMID: 26316326; Falk MJ et al., PMID: 22842227; Huan J et al., PMID: 34243968; Perrault I et al., PMID: 22842229). This variant is only observed on 14/282,780 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Functional studies that measured NAD+ production of the p.Arg237Cys variant resulted in marginally reduced enzymatic activity (Falk MJ et al., PMID: 22842227; Sasaki Y et al., PMID: 26018082). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to NMNAT1 function. This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters and likely pathogenic variant by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.