ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1671_1673GGA[2] (p.Glu561_Glu562del) (rs397517848)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618382 SCV000740107 uncertain significance Cardiovascular phenotype 2017-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768806 SCV000900178 uncertain significance Cardiomyopathy 2016-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000766518 SCV000236150 uncertain significance not provided 2018-06-24 criteria provided, single submitter clinical testing The c.1677_1682delGGAGGA variant in the NEXN gene has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. This variant results in a deletion of two Glutamic acid residues at codons 561 and 562, denoted p.Glu561_Glu562del. These two Glutamic acid residues are class conserved throughout evolution. One in-frame deletion (c.1949_1951delGAG) in the NEXN gene has been reported in association with DCM. Also, c.1677_1682delGGAGGA was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.
Invitae RCV000466420 SCV000560170 likely benign Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2017-12-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.
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.

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