Submissions for variant NM_144573.4(NEXN):c.1955A>G (p.Tyr652Cys)

gnomAD frequency: 0.00011  dbSNP: rs137853197

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041170	SCV000064861	uncertain significance	not specified	2016-09-01	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr652Cys variant in NEXN has been reported in 2 individuals with DCM and 1 Caucasian inf ant with DCM (Hassel 2009, LMM data). This variant has also been identified in 1 1/66220 European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs137853197). Animal models in zebrafish have show n that this variant affects protein function and can lead to dilation of heart t issue (Hassel 2009). Computational prediction tools and conservation analysis su ggest that the p.Tyr652Cys variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr 652Cys variant is uncertain.
GeneDx	RCV000183674	SCV000236143	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Functional studies suggest this missense variant acts in a dominant-negative manner and leads to a dilated cardiomyopathy phenotype in zebrafish (Hassel et al., 2009), however, further functional evidence is needed to clarify the role of this variant in human disease; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20970104, 31028938, 26187847, 27171814, 23299917, 19881492, 29253866, 26383259, 30847666, 33949776, 29961767, 24503780, 34363016, 35166435, 36935760)
Blueprint Genetics	RCV000208290	SCV000264127	likely pathogenic	Primary dilated cardiomyopathy	2015-09-29	criteria provided, single submitter	clinical testing
Invitae	RCV000234084	SCV000291369	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2022-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 652 of the NEXN protein (p.Tyr652Cys). This variant is present in population databases (rs137853197, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19881492, 24503780, 29253866, 30847666). ClinVar contains an entry for this variant (Variation ID: 326). 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"). Experimental studies have shown that this missense change affects NEXN function (PMID: 19881492). 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.
Ambry Genetics	RCV000246924	SCV000319903	uncertain significance	Cardiovascular phenotype	2022-10-24	criteria provided, single submitter	clinical testing	The p.Y652C variant (also known as c.1955A>G), located in coding exon 12 of the NEXN gene, results from an A to G substitution at nucleotide position 1955. The tyrosine at codon 652 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals from cohorts with dilated cardiomyopathy, non-compaction cardiomyopathy and sudden cardiac death, sometimes in conjunction with variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Hassel D et al. Nat. Med., 2009 Nov;15:1281-8; Klauke B et al. PLoS ONE, 2017 Dec;12:e0189489; Hertz CL et al. Int. J. Legal Med., 2016 Jan;130:91-102; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet, 2013 Sep;21:918-28). One functional study indicated that p.Y652C overexpression in zebrafish disrupts sarcomeric units and destabilizes Z-disks, but the clinical relevance of this overexpression study is unclear (Hassel D et al. Nat Med. 2009;15(11):1281-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170736	SCV001333339	uncertain significance	Cardiomyopathy	2022-04-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000354	SCV001519772	uncertain significance	Dilated cardiomyopathy 1CC		criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000000354	SCV001754764	likely pathogenic	Dilated cardiomyopathy 1CC	2020-06-11	criteria provided, single submitter	clinical testing	The c.1955A>G (p.Tyr652Cys) variant in the exon 13 of NEXN gene has been reported in 3 individuals with dilated cardiomyopathy (DCM) and 1 individual with sudden cardiac death (SCD) and non-diagnostic right ventricular hypertrophy (PMID: 19881492, 24503780, 26383259). This variant is present at a frequency of 22/279940 in the population database gnomAD suggesting that it could exhibit reduced penetrance. Multiple lines of in silico algorithms have predicted the p.Tyr652Cys change to be deleterious. Functional studies showed that expression of this variant in zebrafish destabilizes cardiac Z-disks and leads to a DCM phenotype (PMID: 19881492). Therefore, this c.1955A>G (p.Tyr652Cys) in the NEXN gene is classified as likely pathogenic with possible reduced penetrance.
Baylor Genetics	RCV003147270	SCV003835906	pathogenic	Hypertrophic cardiomyopathy 20	2022-10-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000183674	SCV004235587	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing
OMIM	RCV000000354	SCV000020498	pathogenic	Dilated cardiomyopathy 1CC	2009-11-01	no assertion criteria provided	literature only
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491470	SCV000298131	likely pathogenic	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	research