Submissions for variant NM_144573.4(NEXN):c.1573GAA[3] (p.Glu528del)

dbSNP: rs764505909

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000656930	SCV000225714	uncertain significance	not provided	2014-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000656930	SCV000236114	uncertain significance	not provided	2024-02-04	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid in a repetitive region with no known function; This variant is associated with the following publications: (PMID: 26582918, 37298070)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183645	SCV000272211	uncertain significance	not specified	2015-06-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu528del variant has been identified in 2 consanguineous families of Middle Eastern anc estry as homozygous in 5 affected siblings (Conference abstract by Al-Hassnan 20 13, LMM unpublished data). This variant has also been identified as heterozygous in 14/65856 European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org). This variant is a deletion of 1 amino acid at posi tion 528 from a string of 4 glutamic acids. It is unclear if this deletion will impact the protein. In summary, while there is some suspicion for a pathogenic r ole, the clinical significance of the p.Glu528del variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647277	SCV000769066	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2024-01-27	criteria provided, single submitter	clinical testing	This variant, c.1582_1584del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Glu528del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770868024, gnomAD 0.03%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 31568572; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1572_1574delAGA (p.E525del). ClinVar contains an entry for this variant (Variation ID: 194130). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV000769827	SCV000901253	uncertain significance	Cardiomyopathy	2020-05-13	criteria provided, single submitter	clinical testing
Klaassen Lab, Charite University Medicine Berlin	RCV000853115	SCV000995826	uncertain significance	Primary dilated cardiomyopathy	2019-07-03	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000656930	SCV002542274	uncertain significance	not provided	2021-07-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390422	SCV002703855	uncertain significance	Cardiovascular phenotype	2022-11-22	criteria provided, single submitter	clinical testing	The c.1582_1584delGAA variant (also known as p.E528del) is located in coding exon 11 of the NEXN gene. This variant results from an in-frame GAA deletion at nucleotide positions 1582 to 1584. This results in the in-frame deletion of a glutamic acid at codon 528. This variant was reportedly detected in the homozygous state in two siblings with severe, pediatric onset dilated cardiomyopathy (Bruyndonckx L et al. Am J Med Genet A. 2021 08;185(8):2464-2470). This variant, also referred to as p.E525del, was detected in a homozygous proband with DCM and in the heterozygous state in a proband with DCM and noncompaction cardiomyopathy who was also homozygous for a variant in the TNNI3 gene (Kühnisch J. Clin Genet. 2019 12;96(6):549-559). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000647277	SCV002785898	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2021-09-08	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338444	SCV004046933	uncertain significance	Dilated cardiomyopathy 1CC		criteria provided, single submitter	clinical testing	The inframe deletion c.1582_1584del (p.Glu528del) has been observed in individual(s) with dilated cardiomyopathy (Kuhnisch J, et.al.,2019).This variant has been reported to the ClinVar database as Uncertain Significance. The p.Glu528del variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.01535% is reported in gnomAD. This p.Glu528del causes deletion of amino acid Glutamic Acid at position 528. For these reasons, this variant has been classified as Uncertain Significance .
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003338444	SCV004807261	uncertain significance	Dilated cardiomyopathy 1CC	2024-03-26	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000656930	SCV005186766	uncertain significance	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000656930	SCV001742865	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000183645	SCV001919886	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656930	SCV001955753	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656930	SCV001964474	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734778	SCV005353932	uncertain significance	NEXN-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The NEXN c.1582_1584delGAA variant is predicted to result in an in-frame deletion (p.Glu528del). This variant, also described as c.1572_1574delAGA, has been reported in the homozygous state in at least five individuals with dilated cardiomyopathy (DCM) including two sibling pairs (Al-Hassnan et al. 2013. DOI: 10.1016/j.jsha.2013.03.180; Tables S4 & S5, Kühnisch et al. 2019. PubMed ID: 31568572; Al Mansoori et al. 2023. PubMed ID: 37298070). It has also been reported in the heterozygous state in an individual with DCM and left ventricular non-compaction (LVNC) who was homozygous for a splice-altering, loss-of-function variant in the TNNI3 gene (Tables S4 & S5, Kühnisch et al. 2019. PubMed ID: 31568572). This variant is reported in 0.036% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.