ClinVar Genomic variation as it relates to human health

A variant of uncertain significance has been identified in the TTN gene. The P30759T variant (reported as P29832T due to the use of alternate nomenclature) has been published two patients with sudden unexplained death (SUD), however, both of these patients harbored additional cardiogenetic variants (Campuzano et al., 2014; Sanchez et al., 2016). The P30759T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P30759T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this is a missense variant in a gene in which most reported pathogenic variants associated with cardiomyopathy are truncating/loss-of-function (Stenson et al., 2014).

The p.Pro29832Thr variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/11470 of Latino chromosomes a nd 10/65646 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs373876117). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro29832Thr varia nt is uncertain.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Variant summary: TTN c.89494C>A (p.Pro29832Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 242672 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00012 vs 0.00039), allowing no conclusion about variant significance. c.89494C>A has been reported in the literature in individuals affected with sudden cardiac death or sudden unexplained death with other co-occurring variants (Campuzano_2014, Sanchez_2016, Martinez_2023). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25447171, 36693943, 27930701). ClinVar contains an entry for this variant (Variation ID: 229551). Based on the evidence outlined above, the variant was classified as uncertain significance.

The c.70003C>A (p.P23335T) alteration is located in exon 177 (coding exon 176) of the TTN gene. This alteration results from a C to A substitution at nucleotide position 70003, causing the proline (P) at amino acid position 23335 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.