NM_144573.4(NEXN):c.1955A>G (p.Tyr652Cys) AND Dilated cardiomyopathy 1CC

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jul 17, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000000354.8

Allele description [Variation Report for NM_144573.4(NEXN):c.1955A>G (p.Tyr652Cys)]

NM_144573.4(NEXN):c.1955A>G (p.Tyr652Cys)

Gene:

NEXN:nexilin F-actin binding protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_144573.4(NEXN):c.1955A>G (p.Tyr652Cys)

Other names:

p.Y652C:TAT>TGT

HGVS:

NC_000001.11:g.77942756A>G
NG_016625.1:g.59242A>G
NG_033243.2:g.41338T>C
NM_001172309.2:c.1763A>G
NM_144573.4:c.1955A>GMANE SELECT
NP_001165780.1:p.Tyr588Cys
NP_653174.3:p.Tyr652Cys
NP_653174.3:p.Tyr652Cys
LRG_442t1:c.1955A>G
LRG_442:g.59242A>G
LRG_442p1:p.Tyr652Cys
LRG_995:g.41338T>C
NC_000001.10:g.78408441A>G
NM_144573.3:c.1955A>G
Q0ZGT2:p.Tyr652Cys
c.1955A>G

Protein change:

Y588C; TYR652CYS

Links:

UniProtKB: Q0ZGT2#VAR_063011; OMIM: 613121.0002; dbSNP: rs137853197

NCBI 1000 Genomes Browser:

rs137853197

Molecular consequence:

NM_001172309.2:c.1763A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_144573.4:c.1955A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dilated cardiomyopathy 1CC (CMD1CC)
Identifiers:: MONDO: MONDO:0013147; MedGen: C2751084; Orphanet: 154; OMIM: 613122

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020498	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001519772	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001754764	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 11, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086253	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 17, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 19881492, 20970104, 24503780, 26383259, 29253866, 29961767, 31028938, 32814711, 34363016, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy.

Hassel D, Dahme T, Erdmann J, Meder B, Huge A, Stoll M, Just S, Hess A, Ehlermann P, Weichenhan D, Grimmler M, Liptau H, Hetzer R, Regitz-Zagrosek V, Fischer C, Nürnberg P, Schunkert H, Katus HA, Rottbauer W.

Nat Med. 2009 Nov;15(11):1281-8. doi: 10.1038/nm.2037. Epub 2009 Nov 1.

PubMed [citation]

PMID:: 19881492

Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy.

Wang H, Li Z, Wang J, Sun K, Cui Q, Song L, Zou Y, Wang X, Liu X, Hui R, Fan Y.

Am J Hum Genet. 2010 Nov 12;87(5):687-93. doi: 10.1016/j.ajhg.2010.10.002. Epub 2010 Oct 21.

PubMed [citation]

PMID:: 20970104
PMCID:: PMC2978958

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000020498.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 patients with dilated cardiomyopathy (CMD1CC; 613121), Hassel et al. (2009) identified heterozygosity for a 1955A-G transition in the NEXN gene, resulting in a tyr652-to-cys (Y652C) substitution at a highly conserved residue. Both probands had a parent who had died of dilated cardiomyopathy; 1 proband underwent heart transplantation at age 60 years due to progressive dilated cardiomyopathy. The 2 Y652C mutation carriers shared a common haplotype that was distinct from the G650del (613121.0001)-associated haplotype, suggesting a distinct founder effect; the mutation was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. Ultrastructural analysis of myocardial biopsy tissue from a Y652C patient showed disruption of sarcomeric units with detached and blurry Z discs, similar to that seen in NEXN-deficient zebrafish. Ectopic expression of Y652C-mutated nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption. Injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001519772.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001754764.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.1955A>G (p.Tyr652Cys) variant in the exon 13 of NEXN gene has been reported in 3 individuals with dilated cardiomyopathy (DCM) and 1 individual with sudden cardiac death (SCD) and non-diagnostic right ventricular hypertrophy (PMID: 19881492, 24503780, 26383259). This variant is present at a frequency of 22/279940 in the population database gnomAD suggesting that it could exhibit reduced penetrance. Multiple lines of in silico algorithms have predicted the p.Tyr652Cys change to be deleterious. Functional studies showed that expression of this variant in zebrafish destabilizes cardiac Z-disks and leads to a DCM phenotype (PMID: 19881492). Therefore, this c.1955A>G (p.Tyr652Cys) in the NEXN gene is classified as likely pathogenic with possible reduced penetrance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086253.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, functional studies have suggested both dominant negative or loss of function mechanisms (PMID: 19881492, PMID: 20970104, PMID: 32814711). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (33 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated immunoglobulin I-set domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as both a VUS, and as likely pathogenic, and observed in at least 10 individuals with dilated cardiomyopathy (DCM), sudden cardiac death or pancardiomyopathy (ClinVar, cardiodb.org, PMID: 24503780, PMID: 26383259, PMID: 31028938). An additional two individuals had causative variants in either the TTN or MYH7 genes (PMID: 29253866, PMID: 29961767). Another two individuals had ascending aortic aneurysm and dissection, or a family history of cardiac disease, but no indication of DCM themselves (PMID: 34363016). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Overexpression of this variant in zebrafish models has proven it causes disruption to sarcomeric units and destabilizes Z-disks (PMID: 19881492). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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