Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000644448 | SCV000766144 | uncertain significance | Atrial septal defect 7 | 2019-11-25 | criteria provided, single submitter | clinical testing | 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 replaces glutamic acid with alanine at codon 126 of the NKX2-5 protein (p.Glu126Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786393 | SCV000925202 | uncertain significance | not provided | 2017-12-18 | no assertion criteria provided | provider interpretation | NKX2-5, Exon 2, c.377A>C (p.Glu126Ala) (NM_004387.3; chr5-172660170-T-G) Seen in a family in our center with DCM who also have a likely pathogenic A band frameshift in TTN. SCICD Classification: variant of uncertain significance based on limited data to associate this gene with this disease, lack of case data and presence in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: Costa al (2013) were the first to look at NKX2.5 in DCM. They sequenced NKX2.5 in 220 DCM probands and found one missense that they felt was disease causing (1/220), p.Ile184Met. The proband had normal sequencing of key DCM genes. Three family members had DCM and all carried the variant. Another family member had conduction system disease without other cardiac findings and also carried the variant. All of the three family members with DCM also had phenotypes previously associated with NKX2.5 including conduction system disease and congenital heart defects. Yuan et al (2015) sequenced NKX2.5 in 130 probands with DCM and found one suspicious variant, p.Ser146Trp (0.77% frequency). A total of three family members with DCM were positive for the variant. The probands father had DCM and was deceased. The proband's mother tested positive for the variant, suggesting it was inherited from the father. The family phenotype also included atrial fibrillation, atrioventricular block, premature ventricular contractions, and sudden death. Patrick Ellinor's group reported on two families with NKX2.5 variants segregating with cardiac phenotypes, including DCM. In both cases exome sequencing was used to identify the variant. Xu et al (2017) sequenced NKX2.5 in 210 unrelated patients with "sporadic adult-onset" DCM and found suspicious variants in 2 individuals (0.95% frequency). Both had atrial septal defect and progressive atrioventricular block. Interestingly, in both cases the variants were de novo and the parents did not have DCM. Family 186 had p.Ile184Phe, Family 187 had p.Ile184Met (previously reported by Costa et al 2013, absent in gnomAD). Phenotypes in both families included DCM, VSD, ASD, AV block. In family 186 the individuals with DCM did not have the other phenotypes. The variant was present in two affected siblings and their affected uncle. Their mother was also affected. In family 187 the variant was present in a male with DCM, his son with ASD, and his cousin with DCM. Another cousin (different branch) had VSD but did not have the variant (the authors interpreted this as a sporadic phenotype). Another cousin (yet another distinct branch) had polymorphic NSVT in the setting of heavy caffeine intake, but didn't have the variant. Related genes have been reported in association with cardiomyopathy, though we did not assess the strength of evidence (ex. TBX20, GATA4, TBX5, GATA5, HAND1. Case data (not including our patient): none reported Segregation data: none reported Functional data: none reported Population data: Highest MAF in gnomAD Latino population: 0.003034%. The variant was reported online in 1 of 16478 Latino individuals in 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. It was not seen in any other groups in gnomAD. |