ClinVar Miner

Submissions for variant NM_181486.4(TBX5):c.563C>T (p.Ala188Val)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV003994695 SCV004812665 uncertain significance Holt-Oram syndrome 2023-11-05 criteria provided, single submitter clinical testing This sequence change in TBX5 is predicted to replace alanine with valine at codon 188, p.(Ala188Val). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the DNA-binding Tbox domain in a region, amino acids 146-204, that is highly intolerant to missense variation (PMID: 31116477). There is a moderate physicochemical difference between alanine and valine. This variant is present in a single European (non-Finnish) individual from the population database gnomAD v2.1 (1/113,762 alleles). To our knowledge, this variant has not been previously reported in the relevant scientific literature. It has been reported as a variant of uncertain significance (LOVD). Computational evidence is uninformative for the missense substitution (REVEL = 0.639). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PM2_Supporting.

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