Submissions for variant NM_004387.4(NKX2-5):c.335-7C>G

dbSNP: rs937339110

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537452	SCV000644777	uncertain significance	Atrial septal defect 7	2019-02-23	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with NKX2-5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 1 of the NKX2-5 gene. It does not directly change the encoded amino acid sequence of the NKX2-5 protein.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786391	SCV000925200	uncertain significance	not provided	2017-07-24	no assertion criteria provided	provider interpretation	c.335-7C>G in Intron 1 of the NKX2-5 gene (NM_004387.3) Chromosome position 5:172660219 G / C Found in a 4-year-old male with sick sinus syndrome and an ASD vs PFO. We classify this as a Variant of Uncertain Significance (VUS). However, we do want to offer testing to our patient’s other affected family members to see if it segregates with the sick sinus syndrome, ASDs and VSDs present in this family. Of note, it was found alongside a Likely Pathogenic variant in the SCN5A gene which can explain the sick sinus syndrome although not the ASDs and VSDs. This variant has not previously been reported in the literature in association with disease. It is not present in population databases. This variant does not change the encoded amino acid sequence of the NKX2.5 protein. The question is whether it may have an effect on splicing. According to the Invitae report, algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is absent from the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is acceptable sequencing coverage at this site. Over 90% of individuals are covered at 10x and 75% are covered at 20x, with mean coverage of 60x and median coverage of 55x. 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. The curators made an effort to exclude individuals with severe pediatric diseases.