A rare splice-site variant in cardiac troponin-T (TNNT2): The need for ancestral diversity in genomic reference datasets

The underrepresentation of different ancestry groups in large genomic datasets creates difficulties in interpreting the pathogenicity of monogenic variants. Genetic testing for individuals with non-European ancestry results in higher rates of uncertain variants and a greater risk of misclassification. We report a rare variant in the cardiac troponin T gene, TNNT2; NM_001001430.3: c.571-1G>A (rs483352835) identified via research-based whole exome sequencing in two unrelated probands of Oceanian ancestry with cardiac phenotypes. The variant disrupts the canonical splice acceptor site, activating a cryptic acceptor and resulting in an in-frame deletion (p.Gln191del). The variant is rare in gnomAD v4.0.0 (13/780,762; 0.002%), with the highest frequency in South Asians (5/74,486; 0.007%) and has 16 ClinVar assertions (13 diagnostic clinical laboratories classify as variant of uncertain significance). There are at least 28 reported cases, many with Oceanian ancestry and diverse cardiac phenotypes. Indeed, among Oceanian-ancestry-matched datasets, the allele frequency ranges from 2.9-8.8% and is present in 2/4 (50%) Indigenous Australian alleles in Genome Asia 100K, with one participant being homozygous. With Oceanians deriving greater than 3% of their DNA from archaic genomes, we found c.571-1G>A in Vindija and Altai Neanderthal, but not the Altai Denisovan, suggesting an origin post Neanderthal divergence from modern humans 130-145 thousand years ago. Based on these data, we classify this variant as benign, and conclude it is not a monogenic cause of disease. Even with ongoing efforts to increase representation in genomics, we highlight the need for caution in assuming rarity of genetic variants in largely European datasets. Efforts to enhance diversity in genomic databases remain crucial.