Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000620965 | SCV000736658 | likely pathogenic | Cardiovascular phenotype | 2018-02-06 | criteria provided, single submitter | clinical testing | The p.K651* variant (also known as c.1951A>T), located in coding exon 12 of the TTN gene, results from an A to T substitution at nucleotide position 1951. This changes the amino acid from a lysine to a stop codon within coding exon 12. This exon is located in the Z-disk region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). Based on internal structural analysis, this alteration affects the actin binding Z-repeats and is expected to impact downstream actin interactions. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med. 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med. 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet. 2017 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |