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NM_004387.4(NKX2-5):c.550A>C (p.Ile184Leu) AND Atrial septal defect 7

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 15, 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:
RCV003510303.2

Allele description [Variation Report for NM_004387.4(NKX2-5):c.550A>C (p.Ile184Leu)]

NM_004387.4(NKX2-5):c.550A>C (p.Ile184Leu)

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.550A>C (p.Ile184Leu)
HGVS:
  • NC_000005.10:g.173232994T>G
  • NG_013340.1:g.7319A>C
  • NG_106657.1:g.969T>G
  • NG_106658.1:g.89T>G
  • NM_001166175.2:c.*503A>C
  • NM_001166176.2:c.*349A>C
  • NM_004387.4:c.550A>CMANE SELECT
  • NP_004378.1:p.Ile184Leu
  • LRG_671t1:c.550A>C
  • LRG_671:g.7319A>C
  • LRG_671p1:p.Ile184Leu
  • NC_000005.9:g.172659997T>G
Protein change:
I184L
Molecular consequence:
  • NM_001166175.2:c.*503A>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001166176.2:c.*349A>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_004387.4:c.550A>C - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004330791Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Oct 15, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy.

Costa MW, Guo G, Wolstein O, Vale M, Castro ML, Wang L, Otway R, Riek P, Cochrane N, Furtado M, Semsarian C, Weintraub RG, Yeoh T, Hayward C, Keogh A, Macdonald P, Feneley M, Graham RM, Seidman JG, Seidman CE, Rosenthal N, Fatkin D, et al.

Circ Cardiovasc Genet. 2013 Jun;6(3):238-47. doi: 10.1161/CIRCGENETICS.113.000057. Epub 2013 May 9.

PubMed [citation]
PMID:
23661673
PMCID:
PMC3816146

Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families.

Hanley A, Walsh KA, Joyce C, McLellan MA, Clauss S, Hagen A, Shea MA, Tucker NR, Lin H, Fahy GJ, Ellinor PT.

BMC Med Genet. 2016 Nov 17;17(1):83.

PubMed [citation]
PMID:
27855642
PMCID:
PMC5114776
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004330791.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 184 of the NKX2-5 protein (p.Ile184Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NKX2-5 protein function. This variant disrupts the p.Ile184 amino acid residue in NKX2-5. Other variant(s) that disrupt this residue have been observed in individuals with NKX2-5-related conditions (PMID: 23661673, 27855642), which suggests that this may be a clinically significant amino acid residue. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024