NM_004387.4(NKX2-5):c.508C>T (p.Gln170Ter) AND Atrial septal defect 7

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 16, 2023
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:: RCV000009569.10

Allele description [Variation Report for NM_004387.4(NKX2-5):c.508C>T (p.Gln170Ter)]

NM_004387.4(NKX2-5):c.508C>T (p.Gln170Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

5q35.1

Genomic location:

Preferred name:

NM_004387.4(NKX2-5):c.508C>T (p.Gln170Ter)

HGVS:

NC_000005.10:g.173233036G>A
NG_013340.1:g.7277C>T
NM_001166175.2:c.*461C>T
NM_001166176.2:c.*307C>T
NM_004387.4:c.508C>TMANE SELECT
NP_004378.1:p.Gln170Ter
LRG_671t1:c.508C>T
LRG_671:g.7277C>T
LRG_671p1:p.Gln170Ter
NC_000005.9:g.172660039G>A
NM_004387.3:c.508C>T

Protein change:

Q170*; GLN170TER

Links:

OMIM: 600584.0002; dbSNP: rs104893901

NCBI 1000 Genomes Browser:

rs104893901

Molecular consequence:

NM_001166175.2:c.*461C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001166176.2:c.*307C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_004387.4:c.508C>T - nonsense - [Sequence Ontology: SO:0001587]

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 7 with or without atrioventricular conduction defects; 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
SCV000029787	OMIM	no assertion criteria provided	Pathogenic (Jul 3, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000551862	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9651244, 10587520, 21561848, 10948187, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000029787

OMIM

no assertion criteria provided

Pathogenic
(Jul 3, 1998)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000551862

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 16, 2023)

germline

clinical testing

PubMed (5)
[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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Congenital heart disease caused by mutations in the transcription factor NKX2-5.

Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG.

Science. 1998 Jul 3;281(5373):108-11.

PubMed [citation]

PMID:: 9651244

Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.

Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD.

J Clin Invest. 1999 Dec;104(11):1567-73.

PubMed [citation]

PMID:: 10587520
PMCID:: PMC409866

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000029787.4

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

Description

In a 4-generation family with atrial septal defect secundum and atrioventricular conduction defects (ASD7; 108900), Schott et al. (1998) found a heterozygous sequence change in the CSX gene that encoded a truncated NKX2.5 protein. A C-to-T transition at nucleotide 618 was predicted to substitute a termination codon (TAG) for a glutamine (CAG) codon, which would stop translation prematurely at position 33 of the homeodomain. The mutation was designated gln170 to ter (Q170X). One of the 6 affected members of this family also had left ventricular hypertrophy; 2 affected individuals underwent sudden death.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000551862.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Gln170*) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 155 amino acid(s) of the NKX2-5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with congenital heart defects (PMID: 9651244, 10587520, 21561848; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9005). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NKX2-5 function (PMID: 10948187). 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: Sep 29, 2024

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