Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000184242 | SCV000236864 | pathogenic | not provided | 2015-12-02 | criteria provided, single submitter | clinical testing | p.Glu18144Stop (GAG>TAG): c.54430 G>T in exon 251 of the TTN gene (NM_001256850.1). The E18144X mutation in the TTN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. E18144X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, E18144X is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman et al., 2012).In summary, E18144X in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s). |
| Ambry Genetics | RCV002321740 | SCV002610731 | likely pathogenic | Cardiovascular phenotype | 2019-11-01 | criteria provided, single submitter | clinical testing | The p.E10720* variant (also known as c.32158G>T), located in coding exon 128 of the TTN gene, results from a G to T substitution at nucleotide position 32158. This changes the amino acid from a glutamic acid to a stop codon within coding exon 128. This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 01;49:46-53). As such, this alteration is classified as likely pathogenic. |