ClinVar Miner

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

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Total submissions: 4
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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 2019-10-06 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). This variant has not been reported in the literature in individuals with NEXN-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000620168 SCV000737130 uncertain significance Cardiovascular phenotype 2020-04-28 criteria provided, single submitter clinical testing The c.1918_1922delTACTT variant, located in coding exon 12 of the NEXN gene, results from a deletion of five nucleotides at positions 1918 to 1922, causing a translational frameshift with a predicted alternate stop codon (p.Y640Tfs*14). This frameshift occurs at the 3' terminus of NEXN, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 36 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000786389 SCV001783098 uncertain significance not provided 2021-07-01 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 470680; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation as the last 36 amino acids are lost and replaced with 13 incorrect amino acids; however, loss-of-function variants have not been reported downstream of this position in the protein, and the majority of the NEXN variants reported in HGMD are missense variants (Stenson et al., 2014)
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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