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NM_004387.4(NKX2-5):c.673C>T (p.Arg225Cys) AND Atrial septal defect 7

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 18, 2024
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:
RCV001210640.8

Allele description [Variation Report for NM_004387.4(NKX2-5):c.673C>T (p.Arg225Cys)]

NM_004387.4(NKX2-5):c.673C>T (p.Arg225Cys)

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.673C>T (p.Arg225Cys)
HGVS:
  • NC_000005.10:g.173232871G>A
  • NG_013340.1:g.7442C>T
  • NM_001166175.2:c.*626C>T
  • NM_001166176.2:c.*472C>T
  • NM_004387.4:c.673C>TMANE SELECT
  • NP_004378.1:p.Arg225Cys
  • LRG_671t1:c.673C>T
  • LRG_671:g.7442C>T
  • LRG_671p1:p.Arg225Cys
  • NC_000005.9:g.172659874G>A
  • NM_004387.3:c.673C>T
Protein change:
R225C
Links:
dbSNP: rs866974584
NCBI 1000 Genomes Browser:
rs866974584
Molecular consequence:
  • NM_001166175.2:c.*626C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001166176.2:c.*472C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_004387.4:c.673C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001382136Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 18, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

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, SCV001382136.5

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the NKX2-5 protein (p.Arg225Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. ClinVar contains an entry for this variant (Variation ID: 940953). 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. 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: Jan 13, 2025