NM_004387.4(NKX2-5):c.434dup (p.Ser146fs) AND Atrial septal defect 7

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 27, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001895301.5

Allele description [Variation Report for NM_004387.4(NKX2-5):c.434dup (p.Ser146fs)]

NM_004387.4(NKX2-5):c.434dup (p.Ser146fs)

Gene:

NKX2-5:NK2 homeobox 5 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

5q35.1

Genomic location:

Preferred name:

NM_004387.4(NKX2-5):c.434dup (p.Ser146fs)

HGVS:

NC_000005.10:g.173233111dup
NG_013340.1:g.7203dup
NM_001166175.2:c.*387dup
NM_001166176.2:c.*233dup
NM_004387.4:c.434dupMANE SELECT
NP_004378.1:p.Ser146fs
LRG_671t1:c.434dup
LRG_671:g.7203dup
LRG_671p1:p.Ser146fs
NC_000005.9:g.172660112_172660113insA
NC_000005.9:g.172660114dup

Protein change:

S146fs

Links:

dbSNP: rs2113901953

NCBI 1000 Genomes Browser:

rs2113901953

Molecular consequence:

NM_001166175.2:c.*387dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001166176.2:c.*233dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_004387.4:c.434dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Atrial septal defect 7
Synonyms:: Atrial septal defect with atrioventricular conduction defects; ASD WITH OR WITHOUT ATRIOVENTRICULAR CONDUCTION DEFECTS; Atrial septal defect with atrioventricular conduction defects, somatic; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007173; MedGen: C3276096; Orphanet: 1479; OMIM: 108900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002156363	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 27, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22920929, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002156363

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 27, 2021)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Wenckebach periodicity at rest that normalizes with tachycardia in a family with a NKX2.5 mutation.

Guntheroth W, Chun L, Patton KK, Matsushita MM, Page RL, Raskind WH.

Am J Cardiol. 2012 Dec 1;110(11):1646-50. doi: 10.1016/j.amjcard.2012.07.033. Epub 2012 Aug 22.

PubMed [citation]

PMID:: 22920929

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002156363.4

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

Description

This sequence change creates a premature translational stop signal (p.Ser146Leufs*7) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the NKX2-5 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. This variant disrupts a region of the NKX2-5 protein in which other variant(s) (p.Ala262Argfs*32) have been determined to be pathogenic (PMID: 22920929; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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: May 16, 2025

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