ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1053+1G>A (rs397517843)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041156 SCV000064847 uncertain significance not specified 2018-04-27 criteria provided, single submitter clinical testing The c.1053+1G>A variant in NEXN has been identified by our laboratory in 1 infan t with cardiomyopathy and a family history of DCM. This variant did not segregat e with disease in this family, and affected individuals carried another likely p athogenic variant in ATCT1. This variant has been identified in 9/109006 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins; dbSNP rs397517843). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicin g leading to an abnormal or absent protein. NEXN variants have been described i n individuals with DCM and HCM but they are rare and overall poorly studied. In summary, the clinical significance of the c.1053+1G>A variant is uncertain. ACMG /AMP Criteria applied: PP3.
GeneDx RCV000766515 SCV000236126 uncertain significance not provided 2015-04-07 criteria provided, single submitter clinical testing c.1053+1 G>A: IVS9+1 G>A in intron 9 of the NEXN gene (NM_144573.3). Although the c.1053+1 G>A variant has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 9 and is predicted to cause abnormal gene splicing. The c.1053+1 G>A variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, no mutations associated with haploinsuffiency have been reported in the NEXN gene in association with cardiomyopathy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Blueprint Genetics RCV000208507 SCV000264128 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-09-22 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000041156 SCV000740647 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
Invitae RCV000692171 SCV000819982 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2018-04-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the NEXN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs397517843, ExAC 0.003%). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 47886). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NEXN cause disease. 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000766515 SCV001554042 uncertain significance not provided no assertion criteria provided clinical testing The NEXN c.1053+1G>A variant was identified in 1 of 312 proband chromosomes (frequency: 0.0032) from individuals with dilated cardiomyopathy (Walsh_2017_PMID:27532257; Pugh_2014_PMID:24503780). The variant was identified in dbSNP (ID: rs397517843) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Blueprint Genetics, Laboratory for Molecular Medicine and Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute). The variant was identified in control databases in 8 of 246862 chromosomes at a frequency of 0.00003241 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 8 of 110632 chromosomes (freq: 0.000072), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.1053+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the loss of the canonical 5' splice site. However, this has not been confirmed by RNA analysis. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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