Submissions for variant NM_004387.4(NKX2-5):c.809G>A (p.Cys270Tyr)

gnomAD frequency: 0.00003  dbSNP: rs587782931

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617639	SCV000736453	uncertain significance	Cardiovascular phenotype	2024-02-27	criteria provided, single submitter	clinical testing	The p.C270Y variant (also known as c.809G>A), located in coding exon 2 of the NKX2-5 gene, results from a G to A substitution at nucleotide position 809. The cysteine at codon 270 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with a variety of phenotypes, including congenital heart defects, Jervell Lange-Nielsen, and dilated cardiomyopathy, as well as in unaffected family members; some cases also had additional cardiac variants detected (Rauch R et al. J. Med. Genet., 2010 May;47:321-31; Abou Hassan OK et al. Sci Rep, 2015 Mar;5:8848; Uysal F et al. BMC Med. Genet., 2017 10;18:114; Monaco I et al. J Electrocardiol, 2018 Dec;53:40-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644453	SCV000766149	likely benign	Atrial septal defect 7	2024-12-12	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318350	SCV004022076	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP2, PP3, BS2
CeGaT Center for Human Genetics Tuebingen	RCV003430707	SCV004158039	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	NKX2-5: PS4:Moderate, PM6:Supporting, PP3
GeneDx	RCV003430707	SCV005327965	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Identified in a patient with Jervell and Lange-Nielsen syndrome (JLNS) and refractory epilepsy who is also homozygous for a pathogenic KCNQ1 variant (PMID: 29037160); Identified in a patient with DCM and sudden cardiac arrest (PMID: 30611920) and in two patients with Tetralogy of Fallot (ToF) and additonal features (PMID: 19948535); Identified in two siblings with congenital heart disease (CHD) who also harbored variants in other CHD-related genes (PMID: 25742962); the variant was present in the unaffected mother but was absent in a maternal uncle with a personal history of CHD; A published functional study suggests there is no difference in activity between the p.(C270Y) variant and wildtype (PMID: 19948535); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20725931, 34426522, 31824610, 32369864, 19948535, 30611920, 29037160, 25742962)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394498	SCV006053342	uncertain significance	Atrial septal defect 7; Conotruncal heart malformations; Hypothyroidism, congenital, nongoitrous, 5; Tetralogy of Fallot; Ventricular septal defect 3; Hypoplastic left heart syndrome 2	2022-01-04	criteria provided, single submitter	research
Nemer Genomics and Translation Biomedicine Lab, American University of Beirut	RCV000144179	SCV000188643	likely benign	Single ventricle; small Atrial septal defect	2014-01-01	no assertion criteria provided	research