Submissions for variant NM_144573.4(NEXN):c.1671GGA[2] (p.Glu561_Glu562del)

dbSNP: rs397517848

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041163	SCV000064854	uncertain significance	not specified	2014-08-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Glu561_Glu562de l variant in NEXN has been identified by our laboratory in 2 Black individuals ( 1 with cardiomyopathy and PVT and 1 with DCM and VT). This variant has also been identified in 0.2% (7/3591) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs397517848). This variant results in an in-frame deletion of 2 amino acids and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein because the variant spectrum of this gene has not been well characteriz ed. In summary, while the clinical significance of the Glu561_Glu562del variant is uncertain, its frequency suggests that it is more likely to be benign.
GeneDx	RCV000766518	SCV000236150	uncertain significance	not provided	2021-08-06	criteria provided, single submitter	clinical testing	Reported in ClinVar (ClinVar Variant ID# 47893; Landrum et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 24503780, 27532257)
Invitae	RCV001080274	SCV000560170	likely benign	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618382	SCV000740107	likely benign	Cardiovascular phenotype	2019-04-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768806	SCV000900178	likely benign	Cardiomyopathy	2018-11-02	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852586	SCV000995288	likely benign	Long QT syndrome	2018-05-15	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000041163	SCV001433379	likely benign	not specified	2019-08-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964890	SCV004785258	likely benign	NEXN-related condition	2023-11-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766518	SCV000925197	uncertain significance	not provided	2017-10-11	no assertion criteria provided	provider interpretation	Found in a pediatric patient with LVNC who had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9 , ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB , CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Results show that 2 variants were detected: • p.Glu561_Glu562del (c.1677_1682delGGAGGA) in the NEXN gene • p.Ala233Val (c.698C>T) in the MYH7 gene p.Glu561_Glu562del (c.1677_1682delGGAGGA) in exon 13 of the NEXN gene Chromosome location 1:78408154 AGAGGAG / A Based on the data reviewed below, including that this variant is 10x more frequent among individuals with African ancestry such as our patient, we consider this to be a Variant of Uncertain Significance, Probably Benign. This variant results in the in-frame deletion of two Glutamic Acid residues at codons 561 and 562. These two residues are part of a string of 7 Glutamic Acids. These residues are not well conserved across species, but the alternate amino acid is usually Aspartic Acid which is also negatively-charged. LMM reports in ClinVar that they observed this variant in 2 individuals with African ancestry: one with cardiomyopathy and PVT and one with DCM and VT (one case is published in Pugh et al. 2014). This variant was reported in 80 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF 0.03%. Specifically, the variant was observed in 70 individuals with African ancestry (for the highest allele frequency: 0.3%), 6 Latinos, 2 non-Finnish Europeans, and 2 “Other”. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.
Clinical Genetics, Academic Medical Center	RCV000766518	SCV001919059	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766518	SCV001963003	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766518	SCV001977848	likely benign	not provided		no assertion criteria provided	clinical testing