Submissions for variant NM_004387.4(NKX2-5):c.839C>T (p.Pro280Leu)

gnomAD frequency: 0.00009  dbSNP: rs761596254

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526273	SCV000644782	uncertain significance	Atrial septal defect 7	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 280 of the NKX2-5 protein (p.Pro280Leu). This variant is present in population databases (rs761596254, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of NKX2-5-related conditions (PMID: 19533775, 28341588, 35328834). ClinVar contains an entry for this variant (Variation ID: 468246). 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.
Ambry Genetics	RCV000620094	SCV000736377	uncertain significance	Cardiovascular phenotype	2023-09-05	criteria provided, single submitter	clinical testing	The p.P280L variant (also known as c.839C>T), located in coding exon 2 of the NKX2-5 gene, results from a C to T substitution at nucleotide position 839. The proline at codon 280 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an individual with accessory atrioventricular connection, and in individuals from a congenital heart disease and arrhythmia cohorts for whom clinical details were limited (Esposito G et al. Am. J. Med. Genet. A, 2009 Jul;149A:1574-7; Abou Hassan OK et al. Sci Rep. 2015 Mar;5:8848; Proost D et al. J Mol Diagn. 2017 May;19(3):445-459). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003424119	SCV004117543	uncertain significance	NKX2-5-related disorder	2022-12-29	criteria provided, single submitter	clinical testing	The NKX2-5 c.839C>T variant is predicted to result in the amino acid substitution p.Pro280Leu. This variant was reported in an individual with accessory atrioventricular connection (Esposito et al. 2009. PubMed ID: 19533775) and in the heterozygous state in two siblings with thyroid hemiagenesis and in their unaffected father (Szczepanek-Parulska et al. 2022. PubMed ID: 35328834). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-172659708-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV003424118	SCV004158038	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing