NM_004387.4(NKX2-5):c.656C>T (p.Ala219Val) AND Atrial septal defect 7

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 21, 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:: RCV000525369.5

Allele description [Variation Report for NM_004387.4(NKX2-5):c.656C>T (p.Ala219Val)]

NM_004387.4(NKX2-5):c.656C>T (p.Ala219Val)

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.656C>T (p.Ala219Val)

HGVS:

NC_000005.10:g.173232888G>A
NG_013340.1:g.7425C>T
NM_001166175.2:c.*609C>T
NM_001166176.2:c.*455C>T
NM_004387.4:c.656C>TMANE SELECT
NP_004378.1:p.Ala219Val
LRG_671t1:c.656C>T
LRG_671:g.7425C>T
LRG_671p1:p.Ala219Val
NC_000005.9:g.172659891G>A
NM_004387.3:c.656C>T
P52952:p.Ala219Val

Protein change:

A219V; ALA219VAL

Links:

UniProtKB: P52952#VAR_038240; OMIM: 600584.0008; dbSNP: rs104893902

NCBI 1000 Genomes Browser:

rs104893902

Molecular consequence:

NM_001166175.2:c.*609C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001166176.2:c.*455C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_004387.4:c.656C>T - missense variant - [Sequence Ontology: SO:0001583]

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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TSA: Tetralonia malvae s7577_L_18360_0_a_3_6_l_1119 transcribed RNA sequence
TSA: Tetralonia malvae s7577_L_18360_0_a_3_6_l_1119 transcribed RNA sequence
gi|1163965014|gb|GBNI01029296.1||gn :GBNI01|s7577_L_18360_0_a_3_6_l_1119

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000644779	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 21, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15917268, 11714651, 15161646, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000644779

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 21, 2021)

germline

clinical testing

PubMed (4)
[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

Functional dissection of sequence-specific NKX2-5 DNA binding domain mutations associated with human heart septation defects using a yeast-based system.

Inga A, Reamon-Buettner SM, Borlak J, Resnick MA.

Hum Mol Genet. 2005 Jul 15;14(14):1965-75. Epub 2005 May 25.

PubMed [citation]

PMID:: 15917268

NKX2.5 mutations in patients with tetralogy of fallot.

Goldmuntz E, Geiger E, Benson DW.

Circulation. 2001 Nov 20;104(21):2565-8.

PubMed [citation]

PMID:: 11714651

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000644779.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NKX2-5 function (PMID: 15917268). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 9011). This missense change has been observed to co-occur in individuals with a different variant in NKX2-5 that has been determined to be pathogenic (PMID: 15161646), but the significance of this finding is unclear. This missense change has been observed in individuals with Tetralogy of Fallot and ventricular septal defects (PMID: 11714651, 15161646). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 219 of the NKX2-5 protein (p.Ala219Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. 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.

#	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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