Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000617567 | SCV000736679 | likely pathogenic | Cardiovascular phenotype | 2016-09-26 | criteria provided, single submitter | clinical testing | The p.W20409* variant (also known as c.61227G>A), located in coding exon 158 of the TTN gene, results from a G to A substitution at nucleotide position 61227. This changes the amino acid from a tryptophan to a stop codon within coding exon 158, and is located in the A-band region of the N2-B isoform of the titin protein. An alteration of an adjacent nucleotide (c.61226G>A), also resulting in p.W20409*, has been previously detected in a dilated cardiomyopathy (DCM) cohort and was reported to segregate with disease in one family (Akinrinade O et al. Eur Heart J. 2015;36(34):2327-37 (reported as c.88421G>A p.Trp29474* due to alternate transcript nomenclature)). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6005 samples (12010 alleles) with coverage at this position. Truncating alterations in TTN have been observed at a significantly higher frequency among patients with DCM, or 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3 of 231, 1%, P=3x10-16) and healthy controls (7 of 249, 3%, P=9x10-14). Among families with multiple relatives with DCM, studies also provided strong data demonstrating segregation of TTN truncations with disease (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TTN has not been clearly established as a mechanism of disease. As such, this variant is classified as likely pathogenic. |
| Invitae | RCV000642747 | SCV000764434 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2017-12-22 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with TTN-related disease. This sequence change results in a premature translational stop signal in the TTN gene (p.Trp29474*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 6,518 amino acids of the TTN protein. This variant is not present in population databases (ExAC no frequency). This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). A different variant (c.88421G>A) giving rise to the same protein effect observed here (p.Trp29474*) has been reported in individuals with dilated cardiomyopathy (PMID: 26084686), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Likely Pathogenic. |