ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1946_1948GAG[1] (p.Gly650del) (rs397517853)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000251358 SCV000320036 likely pathogenic Cardiovascular phenotype 2016-05-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768810 SCV000900183 uncertain significance Cardiomyopathy 2015-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000766521 SCV000236115 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NEXN gene. The c.1949_1951delGAG variant has beenpublished in several unrelated patients with DCM in one study (Hassel et al., 2009). This variant results in anin-frame deletion of a glycine residue at position 650 of the NEXN gene, which is conserved across species (Hassel etal., 2009). In silico analysis predicts this deletion to be damaging to protein structure/function. However, while otherin-frame deletions in this gene have been reported in the Human Gene Mutation Database in association with DCM(Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Thec.1949_1951delGAG variant is observed in 16/66244 (0.02%) alleles from individuals of European ancestry in theExome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server).
Invitae RCV000470679 SCV000549234 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2016-12-15 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 13 of the NEXN mRNA (c.1949_1951delGAG). This leads to the deletion of 1 amino acid residue in the NEXN protein (p.Gly650del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760927219, ExAC 0.02%). This variant has been reported in six individuals affected with dilated cardiomyopathy. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 19881492). ClinVar contains an entry for this variant (Variation ID: 47899). Experimental studies in zebrafish have shown that expressing NEXN containing this change can recapitulate a dilated cardiomyopathy phenotype (PMID: 19881492). However, the clinical relevance of this observation is uncertain and this effect was also achieved by expressing a different variant that was at an elevated frequency in control individuals. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041169 SCV000064860 uncertain significance not specified 2014-04-04 criteria provided, single submitter clinical testing The Gly650del variant in NEXN removes a single amino acid (glycine) at position 650. The available data on this variant is conflicting. On the one hand, it has been reported in 6 individuals with DCM and was absent from >2500 race-matched c ontrol chromosomes in one study (Hassel 2009). These authors reported that human hearts with this variant had disrupted sarcomeres and abnormal z-discs. Studies in zebrafish embryos also supported that the variant may lead to z-disc disrupt ion and cardiac dilation although it remains unclear if and how this translates to humans. On the other hand the variant has been detected in the general popul ation (NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The reported frequency is high (82/7842 European American chromosomes) but there is concern regarding the accuracy due to an abnormally high ratio of homozygous occ urrences. It is known that zygosity of insertions and deletions is often incorre ct in this data set (personal communication) and therefore the actual frequency of this variant is unknown. It should be noted that pathogenic variants can be p resent at a low frequency in the general population, particularly for diseases w ith clinical variability, reduced penetrance, or recessive inheritance. In summa ry, additional studies are needed to fully access the clinical significance of t his variant.

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