Submissions for variant NM_144573.4(NEXN):c.1174C>T (p.Arg392Ter)

gnomAD frequency: 0.00004  dbSNP: rs750076188

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222720	SCV000272207	uncertain significance	not specified	2015-04-23	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg392X v ariant in NEXN has not been previously reported in individuals with cardiomyopat hy, but has been identified in 1/64806 of European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 392, which is predicted to l ead to a truncated or absent protein. Although the severe nature of this change increases the likelihood that the variant is pathogenic, the NEXN gene has not b een widely studied and the spectrum of variants leading to disease is not well-d efined. Loss of NEXN function has been shown to cause DCM in zebrafish (Hassel 2 009, Wang 2010) and loss of function variants have been identified in individual s with a range of cardiomyopathies (LMM unpublished data); however, it remains u nclear if one or both copies of the gene need to be affected to cause disease. I n summary, while there is some suspicion for a pathogenic role, the clinical sig nificance of the p.Arg392X variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820993	SCV000961732	pathogenic	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg392*) in the NEXN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXN are known to be pathogenic (PMID: 32058062, 32814711, 32870709, 33949776). This variant is present in population databases (rs750076188, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546, 33949776). ClinVar contains an entry for this variant (Variation ID: 229051). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196151	SCV001366672	uncertain significance	Dilated cardiomyopathy 1CC	2019-05-23	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP5.
Loeys Lab, Universiteit Antwerpen	RCV001375648	SCV001572576	uncertain significance	Hypertrophic cardiomyopathy	2021-02-26	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift variant in the NEXN gene (p.(Arg392*)). This variant is present in population databases with a prevalence of 7/276332in GnomAD. Loss of function of NEXN caused DCM in zebrafish (PMID: 19881492). This variant has not been reported in the literature. We identified the variant in 3 unrelated patients: two patients with DCM and one patient with HCM. In the HCM family a second individual with HCM also carried the variant (limited data on segregation:PP1weak). No segregation data are available for the DCM families. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met).
AiLife Diagnostics, AiLife Diagnostics	RCV001357462	SCV002501157	uncertain significance	not provided	2022-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327090	SCV002628807	uncertain significance	Cardiovascular phenotype	2024-08-29	criteria provided, single submitter	clinical testing	The p.R392* variant (also known as c.1174C>T), located in coding exon 9 of the NEXN gene, results from a C to T substitution at nucleotide position 1174. This changes the amino acid from an arginine to a stop codon within coding exon 9. This variant has been detected in the homozygous state in an individual with severe early-onset and fatal dilated cardiomyopathy (DCM) whose heterozygous parents were unaffected (Bruyndonckx L et al. Am J Med Genet A, 2021 08;185:2464-2470). This alteration has also been detected (presumed heterozygous) in individuals from DCM and hypertrophic cardiomyopathy cohorts; however, clinical details were limited and additional alterations in cardiac-related genes were identified in some cases (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; Begay RL et al. JACC Basic Transl Sci. 2016 Aug;1(5):344-359; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487; Boen HM et al. J Heart Lung Transplant. 2022 Sep;41(9):1218-1227). Although biallelic loss of function alterations in NEXN have been associated with autosomal recessive NEXN-related cardiomyopathy, haploinsufficiency for NEXN has not been clearly established as a mechanism of disease for autosomal dominant NEXN-related cardiomyopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive NEXN-related cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant NEXN-related cardiomyopathy is unclear.
Fulgent Genetics, Fulgent Genetics	RCV000820993	SCV002791481	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2021-11-17	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993895	SCV004812262	likely pathogenic	Primary dilated cardiomyopathy	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change in NEXN is a nonsense variant predicted to cause a premature stop codon, p.(Arg392*), in biologically relevant exon 10/16 leading to nonsense-mediated decay in a gene in which there is emerging evidence for loss of function as the mechanism of disease (PMID: 19881492, 26659360, 31983221, 32058062, 32635769, 32814711, 32870709, 33949776, 35166435). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.005% (6/128,186 alleles) in the European (non-Finnish) population, which is consistent with dilated cardiomyopathy (DCM). This variant has been reported heterozygous in at least eight probands with DCM (including one proband with a pathogenic FLNC variant), at least one proband with hypertrophic cardiomyopathy and one proband with an unknown cardiomyopathy (PMID: 25163546, 28008423, 30847666, 31983221, 32880476, 35581137, ClinVar: SCV001572576.1, SCV001366672.2). This variant has been detected homozygous in at least one foetus with hydrops and abnormal cardiac function (PMID: 33949776). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Moderate, PS4_Moderate, PM2_Supporting, PM3_Supporting.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357462	SCV001552942	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NEXN p.Arg392X variant was identified in a study performing NGS on 639 patients with dilated cardiomyopathy (Haas_2014_PMID:25163546). It was not identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs750076188) and Clinvar (classified as a VUS by Laboratory for Molecular Medicine). The variant was identified in control databases in 7 of 280056 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 6 of 128186 chromosomes (freq: 0.000047) and European (Finnish) in 1 of 25012 chromosomes (freq: 0.00004); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Other or South Asian populations. The p.Arg392X variant leads to a premature stop codon at position 392 which is predicted to lead to a truncated or absent protein and loss of function. The role of NEXN loss of function variants in disease is still unclear, however NEXN knock-out mice studies display a cardiomyopathy phenotype (Aherrahrou_2016_PMID:26659360). Further, MutationTaster predicts the variant to be disease-causing (prob: 1). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.