Submissions for variant NM_001029896.2(WDR45):c.183C>A (p.Asn61Lys)

dbSNP: rs2065045729

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001052749	SCV001216974	uncertain significance	Neurodegeneration with brain iron accumulation 5	2019-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with lysine at codon 61 of the WDR45 protein (p.Asn61Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with neurodegeneration with brain iron accumulation (PMID: 23176820, 23687123). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001091505	SCV001247587	pathogenic	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Pediatrics, MediClubGeorgia	RCV001052749	SCV001441624	pathogenic	Neurodegeneration with brain iron accumulation 5	2020-10-31	criteria provided, single submitter	clinical testing	This variant is absent in population databases. This variant has been described in the literature in patient with neurodegeneration with brain ironaccumulation (PMID: 23176820, 23687123).It is also submitted in ClinVar with a conflicting interpretations of pathogenicity​ Pathogenic; Uncertain significance. Parents were also tested and this variant was not detected. Algorithms developed to predict the effect of missense variants showed: Sift- Deleterious, PolyPhen2-HDIV- damaging, PolyPhen2-HVAR-damaging, MutationAssessor- High, MutationTaster- Damaging, Provean - Damaging. The asparagine residue is highly conserved.
Baylor Genetics	RCV001052749	SCV001523780	pathogenic	Neurodegeneration with brain iron accumulation 5		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002409441	SCV002716372	likely pathogenic	Inborn genetic diseases	2018-05-23	criteria provided, single submitter	clinical testing	The p.N61K variant (also known as c.183C>A), located in coding exon 3 of the WDR45 gene, results from a C to A substitution at nucleotide position 183. The asparagine at codon 61 is replaced by lysine, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of WDR45-related neurological disorder (Ambry internal data). This alteration was reported in the literature as a de novo occurrence in an individual with neurodegeneration with brain iron accumulation (Haack TB et al. Am. J. Hum. Genet., 2012 Dec;91:1144-9; Hayflick SJ et al. Brain, 2013 Jun;136:1708-17). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.