Submissions for variant NM_004387.4(NKX2-5):c.356C>A (p.Ala119Glu)

gnomAD frequency: 0.00003  dbSNP: rs369025518

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414455	SCV000491190	uncertain significance	not specified	2016-12-14	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NKX2-5 gene. The A119E variant has been reported in one patient with an atrioventricular septal defect who also harbored a synonymous variant on the same NKX2-5 allele, these variants were inherited from an unaffected mother (Reamon-Buettner et al., 2013). The A119E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies by Reamon-Buettner et al. (2013) using yeast-based assays suggest the presence of the A119E variant may may have a negative impact on sequence-specific transactivation; however, it is not known whether these findings are biological or clinically relevant in vivo. Additionally, this substitution occurs at a position that is not conserved across species and in silico analysis suggests that this variant likely does not alter the protein structure/function. Finally, while a missense variant in the same residue (A119S) has been reported in the Human Gene Mutation Database in association with NKX2-5-related disorders (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000414455	SCV000917902	uncertain significance	not specified	2018-01-24	criteria provided, single submitter	clinical testing	Variant summary: The NKX2-5 c.356C>A (p.Ala119Glu) variant involves the alteration of a non-conserved nucleotide that is not located in a known functional domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/83730 control chromosomes at a frequency of 0.0000239, which is approximately 5 times the estimated maximal expected allele frequency of a pathogenic NKX2-5 variant (0.000005), suggesting this variant may be a benign polymorphism, although this observation needs to be cautiously considered due to the cohort harboring potential individuals with a NKX2-5 phenotype. The variant has been identified in one patient with AVSD, which was inherited from an unaffected mother (Reamon-Buettner_2013). These researchers reported that the variant causes a ~40% reduction in transactivation potential using reporter assays in yeast, suggesting the variant may have an effect on function. One clinical diagnostic laboratory classified this variant as "uncertain significance." Taken together, this variant is classified as a "Variant of Uncertain Significance," until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001321327	SCV001512152	uncertain significance	Atrial septal defect 7	2023-04-22	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects NKX2-5 function (PMID: 24376681). 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. ClinVar contains an entry for this variant (Variation ID: 372743). This missense change has been observed in individual(s) with atrioventricular septal defect (PMID: 24376681). 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 sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 119 of the NKX2-5 protein (p.Ala119Glu).
AiLife Diagnostics, AiLife Diagnostics	RCV002223836	SCV002502069	uncertain significance	not provided	2022-02-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450952	SCV002613528	uncertain significance	Cardiovascular phenotype	2022-08-17	criteria provided, single submitter	clinical testing	The p.A119E variant (also known as c.356C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 356. The alanine at codon 119 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration has been reported in a subject with an atrioventricular septal defect who also carried a second NKX2-5 missense alteration noted to be in cis with p.A119E (Reamon-Buettner SM et al. PLoS One, 2013 Dec;8:e83295). 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.
Fulgent Genetics, Fulgent Genetics	RCV002488852	SCV002783979	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	2021-08-13	criteria provided, single submitter	clinical testing