ClinVar

Description

The p.Leu37Leu variant in NKX2-5 has not been previously reported in patients an d has been identified in 1/110,814 of chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs746594822). Although this v ariant has been seen once in the general population, its frequency is not high e nough to rule out a pathogenic role. The NKX2-5 gene has been associated with va rious congenital heart defects. To date, two different missense variants in NKX2 -5 have been reported in two individuals with hypoplastic left heart syndrome, o ne of which was also identified in a family member with atrial septal defect (El liott 2003 and McElhinney 2003). Although the variant is silent with no predicte d change in amino acid sequence, computational tools predict with moderate stren gth a possible new splice site which could lead to loss of a substantive portion of the protein. It should be noted that this is an unvalidated prediction only, without biological support, and therefore one cannot assume a splicing impact. In summary, the clinical significance of the c.111G>A variant is uncertain at th is time but we cannot rule out pathogenicity of this variant and possible contri bution to the hypoplastic left heart phenotype observed in this patient.