Submissions for variant NM_022787.4(NMNAT1):c.634G>A (p.Val212Met)

gnomAD frequency: 0.00004  dbSNP: rs201994921

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001090804	SCV001246534	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376488	SCV001573654	uncertain significance	Leber congenital amaurosis 9	2021-04-08	criteria provided, single submitter	research	The NMNAT1 c.634G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3-S. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Invitae	RCV001376488	SCV001588903	pathogenic	Leber congenital amaurosis 9	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 212 of the NMNAT1 protein (p.Val212Met). This variant is present in population databases (rs201994921, gnomAD 0.01%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 25412400, 28453600, 29074561). 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: 871051). 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 not expected to disrupt NMNAT1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001090804	SCV001826600	likely pathogenic	not provided	2020-12-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27422788, 27375279, 28453600, 29074561, 25412400, 31054281)
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001376488	SCV004809840	uncertain significance	Leber congenital amaurosis 9	2024-04-04	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001376488	SCV001759973	pathogenic	Leber congenital amaurosis 9		no assertion criteria provided	clinical testing