ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.893C>G (p.Thr298Arg) (rs200753280)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246908 SCV000317745 uncertain significance Cardiovascular phenotype 2017-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000308250 SCV000492839 uncertain significance Hypertrophic cardiomyopathy 2015-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000041186 SCV000589469 likely benign not specified 2017-10-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000406320 SCV000358977 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000308250 SCV000358978 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000456968 SCV000549238 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2016-08-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 298 of the NEXN protein (p.Thr298Arg). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is present in population databases (rs200753280, ExAC 0.02%) but has not been reported in the literature in individuals with a NEXN-related disease. ClinVar contains an entry for this variant (Variation ID: 47914). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041186 SCV000064877 uncertain significance not specified 2015-09-09 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr298Arg var iant in NEXN has been identified by our laboratory in 1 Ashkenazi Jewish adult w ith HCM and 1 Caucasian adult with HCM. It has also been identified in 12/66354 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs200753280). Threonine at position 298 is not conserved i n evolution and 1 mammal (mouse) has an arginine (Arg) at this position, raising the possibility that this change may be tolerated. In summary, while the clinic al significance of the p.Thr298Arg variant is uncertain, these data suggest that it is more likely to be benign.

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