ClinVar Miner

Submissions for variant NM_022787.4(NMNAT1):c.769G>A (p.Glu257Lys) (rs150726175)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255806 SCV000322385 pathogenic not provided 2018-04-05 criteria provided, single submitter clinical testing The E257K variant in the NMNAT1 gene is one of the most common pathogenic variants and has been reported previously in multiple families with Leber congenital amaurosis when present in the homozygous state or when in trans with another disease-causing variant (Chiang et al., 2012; Koenekoop et al., 2012; Perrault et al., 2012). Additionally, the E257K variant has been reported in an individual with cone-rod dystrophy who harbored an additional disease-causing NMNAT1 variant in trans (Nash et al., 2018). This variant has also been reported in the homozygous state in a single unaffected individual, leading the authors to suggest that this variant may display reduced penetrance (Siemiatkowska et al., 2014). The E257K variant is observed in 193/276,988 (0.069%) total alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The E257K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Significantly lower levels of NAD were observed in an affected individual who was homozygous for the E257K variant (Koenekoop et al., 2012). Additionally, in vitro functional studies demonstrate that the E257K variant affects protein folding and results in a less stable protein under thermal stress; NMNAT1 protein harboring this variant demonstrates significantly reduced enzymatic activity and is less effective at preventing axonal degeneration in HEK293T cells compared to wild-type protein (Koenekoop et al., 2012; Sasaki et al., 2015). We interpret E257K as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255806 SCV000574740 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Invitae RCV000030765 SCV000639245 pathogenic Leber congenital amaurosis 9 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 257 of the NMNAT1 protein (p.Glu257Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs150726175, ExAC 0.1%). This variant has been reported as homozygous, compound heterozygous, and heterozygous in multiple individuals and families affected with Leber congenital amaurosis (LCA), retinitis pigmentosa, and cone-rod dystrophy (PMID: 22842231, 24940029, 22842229, 27032803, 22842227, 22842230, 24625443, 23040504, 26103963). It is considered one of the most common LCA mutations in individuals of European descent (PMID: 22842230). It has been reported in a family with 2 unaffected members that were homozygous for this variant (PMID: 24830548). This observation suggests that this variant may be hypomorphic and disease causing if it is in trans with another, more severe mutation or, if homozygous, its pathogenicity may be dependent on the function of cis acting elements that have yet to be discovered (PMID: 24830548). ClinVar contains an entry for this variant (Variation ID: 37134). Experimental studies have shown that this variant causes a reduction in substrate affinity, reduced protein stability, and loss of enzymatic activity after heat shock (PMID: 26018082). Additionally, it has been reported to cause a reduction in enzymatic activity for NAD biosynthesis and prevents axonal degregation less than wild type NMNAT1 protein. (PMID: 26018082, 22842230). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000504859 SCV000712179 pathogenic Leber congenital amaurosis 2016-06-16 criteria provided, single submitter clinical testing The p.Glu257Lys variant in NMNAT1 has been reported in >20 compound heterozygous individuals with Leber congenital amaurosis (LCA) and was the most frequent NMN AT1 variant identified in patients (Chiang 2012, Falk 2012, Koenekoop 2012, Perr ault 2012, Siemiatkowska 2014). In addition, in vitro functional studies provide some evidence that the p.Glu257Lys variant may impact protein function (Sasaki 2015). This variant has also been identified in 0.06% (74/120,500) of chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs150726175). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. However, available data suggests that this variant only causes disease when the re is a severe pathogenic variant on the opposite allele (Siemiatkowska 2014). I ndividuals homozygous for this variant are not expected to be affected with LCA. In summary, the p.Glu257Lys variant meets our criteria to be classified as pat hogenic for LCA in an autosomal recessive manner based upon its identification i n affected individuals in trans with other disease-associated variants, low freq uency in controls, and functional evidence.
Fulgent Genetics,Fulgent Genetics RCV000030765 SCV000893165 pathogenic Leber congenital amaurosis 9 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075816 SCV001241452 pathogenic Retinal dystrophy 2019-07-19 criteria provided, single submitter clinical testing
OMIM RCV000030765 SCV000053426 pathogenic Leber congenital amaurosis 9 2012-09-01 no assertion criteria provided literature only
GeneReviews RCV000030765 SCV000086988 pathologic Leber congenital amaurosis 9 2013-05-02 no assertion criteria provided curation Converted during submission to Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504859 SCV000599056 likely pathogenic Leber congenital amaurosis 2015-01-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV000504859 SCV001161153 pathogenic Leber congenital amaurosis 2019-06-23 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003567 SCV001161928 likely pathogenic Global developmental delay; Diarrhea; Nystagmus; Retinal dystrophy; Severe visual impairment; Developmental regression; Gastrointestinal dysmotility no assertion criteria provided research

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