ClinVar Genomic variation as it relates to human health

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17668378, 31589614)

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 152 of the TBX20 protein (p.Ile152Met). This variant is present in population databases (rs137852954, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital heart disease (PMID: 17668378). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4632). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TBX20 protein function. Experimental studies have shown that this missense change affects TBX20 function (PMID: 17668378, 19762328). 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.

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS3_SUP,PS4_SUP,PP3.

The p.I152M variant (also known as c.456C>G), located in coding exon 3 of the TBX20 gene, results from a C to G substitution at nucleotide position 456. The isoleucine at codon 152 is replaced by methionine, an amino acid with highly similar properties. This variant was detected in a family with a history of congenital heart defects, including the proband with an atrial septal defect, her mother with a large patent foramen ovale, and her maternal grandmother with a small ventricular septal defect (Kirk EP et al. Am J Hum Genet, 2007 Aug;81:280-91). This variant was also detected in a pediatric dilated cardiomyopathy cohort; however, the affected case reportedly had confirmed GM1 gangliosidosis and was also homozygous for a GLB1 mutation (Herkert JC et al. Genet Med, 2018 11;20:1374-1386). Limited functional studies suggested reduced function, but the clinical impact is uncertain (Kirk EP et al. Am J Hum Genet, 2007 Aug;81:280-91; Posch MG et al. J Med Genet, 2010 Apr;47:230-5). This amino acid position is highly 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.