Submissions for variant NM_144573.4(NEXN):c.1416AAG[1] (p.Arg475del)

dbSNP: rs794729091

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704886	SCV000236148	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Reported in an individual with DCM (Gigli et al., 2019); described as c.1416_1418delAAG (p.Arg475del); In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31514951)
Ambry Genetics	RCV000249380	SCV000318850	likely benign	Cardiovascular phenotype	2020-09-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458753	SCV000549235	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2023-12-11	criteria provided, single submitter	clinical testing	This variant, c.1419_1421del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Arg475del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766608869, gnomAD 0.02%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 31514951). ClinVar contains an entry for this variant (Variation ID: 201940). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845464	SCV000987555	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170730	SCV001333333	uncertain significance	Cardiomyopathy	2019-03-01	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001704886	SCV005199052	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV001704886	SCV006060728	likely benign	not provided	2024-09-19	criteria provided, single submitter	clinical testing	The NEXN c.1419_1421del (p.Arg475del) variant identified in this individual was previously classified as a variant of uncertain significance on the original report issued 06/05/2023. Since the original reporting of this variant, updated population data indicates that this variant is present in the population at an allele frequency higher than expected for a pathogenic variant. This variant has been identified in 7/6084 Middle Eastern chromosomes (196/1613672 chromosomes overall) by the Genome Aggregation Database v4.1.0 (http://gnomad.broadinstitute.org/). This additional information provides sufficient evidence to update the classification of the NEXN c.1419_1421del (p.Arg475del) variant to likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183679	SCV000280399	uncertain significance	not specified	2013-05-22	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Arg474del (c.1419_1421delAAG) This variant is novel. This variant is located in exon 11 (coding exon 10) of the NEXN gene. The variant results from an in-frame AAG deletion between nucleotide position 1419 and 1421. This results in the deletion of an arginine residue at codon 474. The arginine at codon 474 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 474 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 8/1/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 8/1/13). Ambry genetics did not include internal control data.
PreventionGenetics, part of Exact Sciences	RCV004734808	SCV005346561	uncertain significance	NEXN-related disorder	2024-07-15	no assertion criteria provided	clinical testing	The NEXN c.1419_1421delAAG variant is predicted to result in an in-frame deletion (p.Arg475del). This variant was reported in individuals with dilated cardiomyopathy or sudden death; however, no additional studies were performed to help assess the pathogenicity of this variant (Scheiper et al. 2018. PubMed ID: 30415094; Online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; described as c.1416_1418delAAG in Online Table 1, Gigli et al. 2019. PubMed ID: 31514951). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/201940). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.