Submissions for variant NM_144573.4(NEXN):c.1453G>A (p.Glu485Lys)

gnomAD frequency: 0.00006  dbSNP: rs368812830

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041161	SCV000064852	uncertain significance	not specified	2014-02-13	criteria provided, single submitter	clinical testing	The Glu485Lys variant in NEXN has not been reported in the literature but has be en observed in our laboratory in 2 individuals with cardiomyopathy, one with HCM and a second pathogenic variant in MYBPC3 and this individual. This variant h as also been observed in 2/6536 European American chromosomes in a broad and not well clinically characterized population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gl u485Lys variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. In summary, additional data is needed to f ully assess the clinical significance of the Glu485Lys variant.
CeGaT Center for Human Genetics Tuebingen	RCV000994029	SCV001147319	uncertain significance	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV001039945	SCV001203496	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2022-03-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 485 of the NEXN protein (p.Glu485Lys). This variant is present in population databases (rs368812830, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 47891). 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: "Deleterious"; 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798220	SCV002043704	uncertain significance	Cardiomyopathy	2020-09-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001039945	SCV002790324	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2022-05-12	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257941	SCV001434751	uncertain significance	Primary dilated cardiomyopathy		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000994029	SCV001741584	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000994029	SCV001924590	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000994029	SCV001927798	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000994029	SCV001979456	uncertain significance	not provided		no assertion criteria provided	clinical testing