Submissions for variant NM_181486.4(TBX5):c.1485del (p.Thr496fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002389570	SCV002701617	likely pathogenic	Cardiovascular phenotype	2023-09-15	criteria provided, single submitter	clinical testing	The c.1485delG variant, located in coding exon 8 of the TBX5 gene, results from a deletion of one nucleotide at nucleotide position 1485, causing a translational frameshift with a predicted alternate stop codon (p.T496Lfs*86). This alteration occurs at the 3' terminus of theTBX5 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 62 amino acids. This frameshift impacts the last 23amino acids of the native protein. However, frameshifts are typically deleterious in nature. This alteration has been reported in subjects with features of Holt-Oram syndrome and has been noted to segregate with disease (Ambry internal data; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003647921	SCV004432837	likely pathogenic	Aortic valve disease 2	2023-02-11	criteria provided, single submitter	clinical testing	Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This sequence change results in a frameshift in the TBX5 gene (p.Thr496Leufs*86). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the TBX5 protein and extend the protein by 62 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with Holt-Oram syndrome (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1773653). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.