Submissions for variant NM_004387.4(NKX2-5):c.65A>C (p.Gln22Pro)

dbSNP: rs201442000

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542359	SCV000644780	uncertain significance	Atrial septal defect 7	2023-03-03	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: 17544441). 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: 468245). This missense change has been observed in individual(s) with Tetrology of Fallot (PMID: 14607454). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 22 of the NKX2-5 protein (p.Gln22Pro).
AiLife Diagnostics, AiLife Diagnostics	RCV000786392	SCV002501129	uncertain significance	not provided	2022-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002377106	SCV002667193	uncertain significance	Cardiovascular phenotype	2022-03-24	criteria provided, single submitter	clinical testing	The p.Q22P variant (also known as c.65A>C), located in coding exon 1 of the NKX2-5 gene, results from an A to C substitution at nucleotide position 65. The glutamine at codon 22 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a congenital heart disease cohort and one study suggests that this alteration may have an impact on protein function (McElhinney DB et al. J Am Coll Cardiol, 2003 Nov;42:1650-5; Li T et al. J Mol Biol, 2007 Jul;370:976-92). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483450	SCV002793216	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	2021-11-02	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786392	SCV000925201	uncertain significance	not provided	2017-11-06	no assertion criteria provided	provider interpretation	p.Gln22Pro ( c.65A>C) in exon 1 of the NKX2-5 gene (NM_004387.3; chr5-172662022-T-G) SCICD Classification: variant of uncertain significance based on limited data to associate this gene with disease, lack of case data and sufficiently rare. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in a family with arrhythmic cardiomyopathy (DCM/ARVC). Population data: Highest MAF in Latino population: 0.002987% (gnomAD 1/16742). GnomAD overall: 1/119469 individuals. The Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Another variant at the same codon, p.Gln22Arg has been seen in gnomAD with an MAF of 0.02230% in non-Finnish Europeans (27/60546 individuals).