ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1946GAG[1] (p.Gly650del) (rs397517853)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041169 SCV000064860 uncertain significance not specified 2019-12-10 criteria provided, single submitter clinical testing The p.Gly650del variant in NEXN has been reported in the literature in 6 individuals with DCM. Currently there is insufficient evidence to conclude whether this variant segregates with disease in these families (Hassel 2009). This variant has also been identified by other clinical laboratories in 2 individuals with DCM (including an infant whose unaffected mother also harbored this variant), 1 individual with HCM, and 1 individual with an unspecified cardiomyopathy and segregated with DCM in one affected relative from one family (Ambry pers. comm, Invitae pers. comm., LMM data, ClinVar Variation ID # 47899). However, it has been identified in 0.02% (27/127614) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/), which is a frequency defined by the ClinGen Inherited Cardiomyopathy Expert Panel Functional as being greater than expected for the disorder. Studies have shown that human hearts with this variant had disrupted sarcomeres and abnormal z-discs and this was also observed in zebrafish embryos injected with this variant that went on to develop severe cardiac dilation (Hassel 2009). This variant is a deletion of 1 amino acid at position 650 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary due to conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PM4_Supporting, BS1_Supporting.
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).
Ambry Genetics RCV000251358 SCV000320036 uncertain significance Cardiovascular phenotype 2020-04-23 criteria provided, single submitter clinical testing The c.1949_1951delGAG variant (also known as p.G650del) is located in coding exon 12 of the NEXN gene. This variant results from an in-frame deletion of 3 nucleotides at positions 1949 to 1951. This results in the in-frame deletions of a glycine residue at codon 650. A previously reported study of 1000 unrelated individuals with dilated cardiomyopathy found 6 individuals that were heterozygous for p.G650del. Functional studies performed in the same study indicated that p.G650del overexpression in zebrafish disrupted sarcomeric units and destabilized Z-disks, but the clinical relevance of the overexpression study is unclear (Hassel D et al. Nat Med. 2009;15(11):1281-8). Based on data from gnomAD, the deletion allele has an overall frequency of approximately 0.01% (29/279530) total alleles studied. The highest observed frequency was 0.11% (3/2662) of Bulgarian alleles. This amino acid position is highly conserved in available vertebrate species; however, the neighboring glycine (p.G649) is poorly conserved. In addition, this alteration is predicted to be deleterious<span style="color:rgb(255, 0, 0)"> by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000470679 SCV000549234 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2020-10-27 criteria provided, single submitter clinical testing This variant, c.1949_1951del, results in the deletion of 1 amino acids of 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%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with dilated cardiomyopathy (PMID: 19881492). ClinVar contains an entry for this variant (Variation ID: 47899). This variant has been reported to affect NEXN protein function (PMID: 19881492). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768810 SCV000900183 uncertain significance Cardiomyopathy 2015-12-01 criteria provided, single submitter clinical testing
Mendelics RCV000986336 SCV001135311 likely benign Dilated cardiomyopathy 1CC 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000766521 SCV001549204 uncertain significance not provided no assertion criteria provided clinical testing The NEXN p.Gly650del variant was identified in 6 of 2000 proband chromosomes (frequency: 0.003) from individuals with dilated cardiomyopathy and was not identified in 2502 control chromosomes from healthy individuals (Hassel_2009_PMID:19881492). No variants were identified in 9 other dilated cardiomyopathy genes in the 6 individuals carrying the p.G650del mutation. The variant was also identified in the mildly affected brother of one of the probands, as well as her 33-year-old unaffected daughter. In two other unrelated probands, both mothers had died of DCM and therefore DNA was unavailable, however both fathers were not carriers, suggesting that the affected mothers are obligate carriers of the p.G650del variant (Hassel_2009_PMID:19881492). The variant was identified in dbSNP (ID: rs1488731300) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Laboratory for Molecular Medicine and CHEO Genetics Diagnostic Laboratory, and as likely pathogenic by Ambry Genetics). The variant was identified in control databases in 29 of 279530 chromosomes at a frequency of 0.0001037 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 27 of 127614 chromosomes (freq: 0.000212), Ashkenazi Jewish in 1 of 10306 chromosomes (freq: 0.000097) and Latino in 1 of 35332 chromosomes (freq: 0.000028), but was not observed in the African, East Asian, European (Finnish), Other or South Asian populations. This variant is an in-frame deletion resulting in the removal of a glycine (gly) residue at codon 650. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Zebrafish with the p.G650del demonstrated a dilated cardiomyopathy phenotype (Hassel_2009_PMID:19881492). 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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