NM_144573.4(NEXN):c.1401AGA[2] (p.Glu470del) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 11, 2024
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:: RCV000041160.9

Allele description [Variation Report for NM_144573.4(NEXN):c.1401AGA[2] (p.Glu470del)]

NM_144573.4(NEXN):c.1401AGA[2] (p.Glu470del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_144573.4(NEXN):c.1401AGA[2] (p.Glu470del)

HGVS:

NC_000001.11:g.77935972AGA[2]
NC_000001.11:g.77935976_77935978del
NG_016625.1:g.52458AGA[2]
NM_001172309.2:c.1209AGA[2]
NM_144573.4:c.1401AGA[2]MANE SELECT
NM_144573.4:c.1407_1409delAGA
NP_001165780.1:p.Glu406del
NP_653174.3:p.Glu470del
LRG_442t1:c.1407_1409del
LRG_442:g.52458AGA[2]
NC_000001.10:g.78401657AGA[2]
NC_000001.10:g.78401657_78401659del
NM_144573.3:c.1405_1407delGAA
NM_144573.3:c.1407_1409del
NM_144573.3:c.1407_1409delAGA
NM_144573.4:c.1407_1409delMANE SELECT
NM_144573.4:c.1407_1409delAGAMANE SELECT
c.1407_1409delAGA

Protein change:

E406del

Links:

dbSNP: rs397517846

NCBI 1000 Genomes Browser:

rs397517846

Molecular consequence:

NM_001172309.2:c.1209AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_144573.4:c.1401AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000064851	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Feb 10, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24503780, 24033266
SCV005039503	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Mar 11, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24503780, 27532257, 32826072 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000064851

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Feb 10, 2015)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005039503

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Mar 11, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	3	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.

Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH.

Genet Med. 2014 Aug;16(8):601-8. doi: 10.1038/gim.2013.204. Epub 2014 Feb 6.

PubMed [citation]

PMID:: 24503780

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064851.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Glu470del variant in NEXN has been identified by our laboratory in 1 infan t with DCM, 1 adult with LVNC (Pugh 2014), and 1 adult with HCM who carried a pa thogenic variant in another gene that was sufficient to explain the disease. Thi s variant has also been identified in 4/16472 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3975 17846). This variant is a deletion of a single amino acid at position 470 and do es not alter the protein reading-frame. It is unclear if this deletion will impa ct protein function. In summary, the clinical significance of the p.Glu470del va riant is uncertain.

#	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		3	not provided	3	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005039503.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: NEXN c.1407_1409delAGA (p.Glu470del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00012 in 1606714 control chromosomes, predominantly at a frequency of ~0.0003 within the African or African-American- and South Asian subpopulations in the gnomAD database (v4.0 dataset), including 1 homozygote. The observed variant frequency within African and South Asian control individuals in the gnomAD database is approximately 20-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEXN causing Dilated Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. c.1407_1409delAGA has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Pugh_2014, Walsh_2017, Pena-Pena_2021), however without providing strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 27532257, 32826072). ClinVar contains an entry for this variant (Variation ID: 47890). Based on the evidence outlined above, the variant was classified as likely 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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