ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1955A>G (p.Tyr652Cys) (rs137853197)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2018-05-18 criteria provided, single submitter clinical testing The Y652C variant in the NEXN gene has previously been reported in two unrelated German patients with DCM (Hassel et al., 2009); these individuals shared a common haplotype, suggesting a possible founder effect. Y652C was also observed in one Danish individual with suspected sudden cardiac death and non-diagnostic right ventricular hypertrophy (Hertz et al., 2016). In addition, this variant has been identified, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. However, for these published cases and cases observed at GeneDx, segregation data are not available and/or not sufficient to further clarify the role of this variant in disease. The Y652C variant is observed in 17/125,922 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).The Y652C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. 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 and segregation studies are needed to clarify the role of this variant in human disease.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
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; Familial hypertrophic cardiomyopathy 20 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 652 of the NEXN protein (p.Tyr652Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs137853197, ExAC 0.02%). This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 19881492, 24503780). ClinVar contains an entry for this variant (Variation ID: 326). Experimental studies have shown that this missense variant destabilizes cardiac Z-disks and leads to a dilated cardiomyopathy phenotype (PMID: 19881492). In summary, this variant has been reported in individuals with dilated cardiomyopathy and it has been shown to affect cardiac Z-disks stability. However, it has also been observed in the general population. For these reasons, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000246924 SCV000319903 likely pathogenic Cardiovascular phenotype 2016-04-23 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Other data supporting pathogenic classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170736 SCV001333339 likely pathogenic Cardiomyopathy 2018-02-27 criteria provided, single submitter clinical testing
OMIM RCV000000354 SCV000020498 pathogenic Dilated cardiomyopathy 1CC 2009-11-01 no assertion criteria provided literature only
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491470 SCV000298131 likely pathogenic Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided research

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