Submissions for variant NM_022787.4(NMNAT1):c.619C>T (p.Arg207Trp)

gnomAD frequency: 0.00004  dbSNP: rs142968179

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000030764	SCV001233664	pathogenic	Leber congenital amaurosis 9	2023-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 207 of the NMNAT1 protein (p.Arg207Trp). This variant is present in population databases (rs142968179, gnomAD 0.007%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 22842229, 22842230, 24940029). 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: 37133). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NMNAT1 protein function. Experimental studies have shown that this missense change affects NMNAT1 function (PMID: 22842230). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001090803	SCV001246533	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001090803	SCV002558377	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme activity (Koenekoop RK1 et al., 2012); 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: 26103963, 28559085, 24940029, 31589614, 34426522, 22842230, 22842229, 26018082)
OMIM	RCV000030764	SCV000053425	pathogenic	Leber congenital amaurosis 9	2012-09-01	no assertion criteria provided	literature only
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV000030764	SCV001433017	pathogenic	Leber congenital amaurosis 9		no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV001090803	SCV001920444	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001090803	SCV001954999	likely pathogenic	not provided		no assertion criteria provided	clinical testing