ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1435C>T (p.Leu479Phe) (rs181520023)

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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 RCV000619532 SCV000740162 uncertain significance Cardiovascular phenotype 2017-06-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000766517 SCV000236132 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The L479F variant of uncertain significance in the NEXN gene has not been published as pathogenic or been reported as benign to our knowledge. 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. The L479F variant is observed in 9/34,408 (0.026%) alleles from individuals of Latino ancestry and 23/126,376 (0.018%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). However, L479F is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Illumina Clinical Services Laboratory,Illumina RCV000384181 SCV000358991 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000287471 SCV000358992 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000535150 SCV000648478 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2017-03-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 479 of the NEXN protein (p.Leu479Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs181520023, 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: 201925). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845501 SCV000987603 uncertain significance Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223852 SCV000280400 uncertain significance not specified 2013-08-25 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.Leu479Phe (c.1435 C>T, L479F) in the NEXN gene (NM_144573.3) Given the lack of case data, the presence in the general population, and the lack of evidence for gene-phenotype relationship, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in association with disease. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (score 0.642). Sift score is 0.95, damaging. The variant was reported online in 3 of 4075 Caucasian individuals and 0 of 1801 African-American individuals in the NHLBI Exome Sequencing Project dataset (per GeneDx report). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012).

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