ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1918_1922del (p.Tyr640fs) (rs1222794437)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536642 SCV000648481 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2017-04-25 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotide in exon 13 of the NEXN mRNA (c.1918_1922delTACTT), causing a frameshift at codon 640. This creates a premature translational stop signal in the last exon of the NEXN mRNA (p.Tyr640Thrfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 36 amino acids of the NEXN protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NEXN-related disease. In summary, this variant is a rare frameshift with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000620168 SCV000737130 likely pathogenic Cardiovascular phenotype 2017-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786389 SCV000925198 uncertain significance not provided 2017-04-25 no assertion criteria provided provider interpretation Found in a 16 year-old male with lone atrial fibrillation and a family history of heart failure and arrhythmias. Testing was done at Invitae. p.Tyr640Thrfs*14 (c.1918_1922delTACTT) in exon 13 of the NEXN gene (NM_144573.3; ENST00000334785) Chromosome position: 1:78408404 TACTT / The NEXN gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant dilated cardiomyopathy (DCM) (MedGen UID: 413929) and hypertrophic cardiomyopathy (HCM) (MedGen UID: 462617). Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease. This is a truncating frameshift variant. According to the Invitae report, it creates a premature translational stop signal in the last exon of the NEXN mRNA. While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 36 amino acids of the NEXN protein. In the ExAC browser, NEXN is given a pLI score (“Probability of Loss-of-Function Intolerance”) of 0.00, indicating that the gene appears tolerant of heterozygous loss of function changes.

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