Submissions for variant NM_004387.4(NKX2-5):c.646del (p.Arg216fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003621020	SCV004435306	pathogenic	Atrial septal defect 7	2023-06-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg216Alafs*16) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 109 amino acid(s) of the NKX2-5 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. This variant disrupts a region of the NKX2-5 protein in which other variant(s) (p.Ala262Argfs*32) have been determined to be pathogenic (PMID: 22920929). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004985493	SCV005453187	likely pathogenic	Cardiovascular phenotype	2024-11-06	criteria provided, single submitter	clinical testing	The c.646delC variant, located in coding exon 2 of the NKX2-5 gene, results from a deletion of one nucleotide at nucleotide position 646, causing a translational frameshift with a predicted alternate stop codon (p.R216Afs*16). This alteration occurs at the 3' terminus of theNKX2-5 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 37% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.