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

gnomAD frequency: 0.00003  dbSNP: rs397517843

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 titute.org; 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	2019-10-08	criteria provided, single submitter	clinical testing	Identified in patients with DCM in the published literature (Pugh et al., 2014; Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 47886; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Canonical splice site variant in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 24503780, 27532257, 31514951)
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692171	SCV000819982	likely pathogenic	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2023-07-14	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 47886). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 31514951). This variant is present in population databases (rs397517843, gnomAD 0.008%). This sequence change affects a donor splice site in intron 9 of the NEXN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEXN are known to be pathogenic (PMID: 32058062, 32814711, 32870709, 33949776).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798218	SCV002043699	uncertain significance	Cardiomyopathy	2019-06-05	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466420	SCV002761533	uncertain significance	Hypertrophic cardiomyopathy 20	2022-04-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000692171	SCV002783310	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2021-10-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537144	SCV004113920	uncertain significance	NEXN-related disorder	2023-08-28	criteria provided, single submitter	clinical testing	The NEXN c.1053+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in individuals with dilated cardiomyopathy phenotypes (Supplemental Table 1, Pugh et al 2014. PubMed ID: 24503780; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Online Table 1, Gigli et al. 2019. PubMed ID: 31514951). This variant is reported in 0.0072% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-78395190-G-A). Loss of function variants in NEXN have been associated with dilated cardiomyopathy phenotypes, variants disrupting canonical splicing sites have not been frequently reported and have conflicting interpretations in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar; HGMD, Human Gene Mutation Database). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004018905	SCV004984298	uncertain significance	Cardiovascular phenotype	2020-11-17	criteria provided, single submitter	clinical testing	The c.1053+1G>A intronic alteration consists of a G to A substitution nucleotides after coding exon 8 in the NEXN gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766515	SCV001930140	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766515	SCV001968897	uncertain significance	not provided		no assertion criteria provided	clinical testing