ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.620A>G (p.Asp207Gly) (rs570946423)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620155 SCV000740042 uncertain significance Cardiovascular phenotype 2019-04-26 criteria provided, single submitter clinical testing The p.D207G variant (also known as c.620A>G), located in coding exon 6 of the NEXN gene, results from an A to G substitution at nucleotide position 620. The aspartic acid at codon 207 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was detected in an individual with hypertrophic cardiomyopathy (HCM) who also had a variant in another cardiac-related gene (Waldmüller S et al. Mol. Cell. Probes. 2015;29:308-14). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Using the BDGP, ESEfinder, and Human Splicing Finder (HSF; Desmet FO et al. Nucleic Acids Res. 2009 May;37(9):e67) splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001240728 SCV001413697 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2019-05-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 207 of the NEXN protein (p.Asp207Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs570946423, ExAC 0.01%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 25979592). ClinVar contains an entry for this variant (Variation ID: 520305). 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: "Benign"; Align-GVGD: "Class C15"). 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. 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.

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