Submissions for variant NM_022787.4(NMNAT1):c.507G>A (p.Trp169Ter)

gnomAD frequency: 0.00012  dbSNP: rs371526758

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255071	SCV000322384	pathogenic	not provided	2019-04-30	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 111 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database(Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22842230, 22842231, 22842229, 29178642, 28559085, 31589614, 32865313)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000030768	SCV001407778	pathogenic	Leber congenital amaurosis 9	2024-10-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp169*) in the NMNAT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 111 amino acid(s) of the NMNAT1 protein. This variant is present in population databases (rs371526758, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 22842229, 22842230, 22842231, 29178642). 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: 265453). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004649113	SCV005146858	pathogenic	Inborn genetic diseases	2024-06-24	criteria provided, single submitter	clinical testing	The c.507G>A (p.W169*) alteration, located in exon 5 (coding exon 4) of the NMNAT1 gene, consists of a G to A substitution at nucleotide position 507. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 169. This alteration occurs at the 3' terminus of the NMNAT1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 40% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (12/282830) total alleles studied. The highest observed frequency was 0.008% (10/129152) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other NMNAT1 variants in individuals with features consistent with NMNAT1-related retinopathy; in at least one instance, the variants were identified in trans (Koenekoop, 2012; Chiang, 2012; Perrault, 2012). Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000030768	SCV000053429	pathogenic	Leber congenital amaurosis 9	2012-09-01	no assertion criteria provided	literature only
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV000030768	SCV001433016	pathogenic	Leber congenital amaurosis 9		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004757984	SCV005359279	pathogenic	NMNAT1-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The NMNAT1 c.507G>A variant is predicted to result in premature protein termination (p.Trp169*). This variant has been reported in the homozygous and compound heterozygous states in individuals with Leber congenital amaurosis (Chiang et al. 2012. PubMed ID: 22842231; Perrault et al. 2012. PubMed ID: 22842229; Koenekoop et al. 2012. PubMed ID: 22842230; Table S4, Stone et al. 2017. PubMed ID: 28559085). This variant has also been reported in the absence of a second NMNAT1 variant in an individual with macular atrophy with pigmentary clumping (Table S3, Perrault et al. 2012. PubMed ID: 22842229). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in NMNAT1 are an established mechanism of disease. This variant is interpreted as pathogenic.