ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1457C>G (p.Ala486Gly)

dbSNP: rs397517847
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000041162 SCV000064853 uncertain significance not specified 2019-03-13 criteria provided, single submitter clinical testing The p.Ala486Gly variant in NEXN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2.
Invitae RCV000816014 SCV000956501 uncertain significance Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20 2018-12-18 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 47892). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 486 of the NEXN protein (p.Ala486Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine.
GeneDx RCV001753451 SCV001987619 uncertain significance not provided 2019-07-19 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 47892; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27532257)
Ambry Genetics RCV003380405 SCV004098172 uncertain significance Cardiovascular phenotype 2023-09-13 criteria provided, single submitter clinical testing The p.A486G variant (also known as c.1457C>G), located in coding exon 10 of the NEXN gene, results from a C to G substitution at nucleotide position 1457. The alanine at codon 486 is replaced by glycine, an amino acid with similar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy cohorts (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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