Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000184256 | SCV000236878 | pathogenic | not provided | 2022-04-13 | criteria provided, single submitter | clinical testing | Published in association with left ventricular noncompaction (LVNC) and early-onset atrial fibrillation (Sedaghat-Hamedani et al., 2017; Choi et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29029073, 30535219, 33190517) |
| Invitae | RCV000554185 | SCV000642459 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg23388*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs781540455, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with atrial fibrillation, dilated cardiomyopathy, and/or left ventricular non-compaction cardiomyopathy (PMID: 29029073, 30535219, 33190517, 34495297, 36264615; Invitae). ClinVar contains an entry for this variant (Variation ID: 202402). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV001000060 | SCV000884780 | pathogenic | not specified | 2018-07-06 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002327000 | SCV002626693 | likely pathogenic | Cardiovascular phenotype | 2023-08-07 | criteria provided, single submitter | clinical testing | The p.R14323* variant (also known as c.42967C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 42967. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 variant (also referred to as NM_001267550:c.70162C>T, p.R23388X) has been detected in a left ventricular non-compaction cohort, an early onset atrial fibrillation cohort, and in an individual with dilated cardiomyopathy (Sedaghat-Hamedani F et al. Eur Heart J, 2017 Dec;38:3449-3460; Choi SH et al. JAMA, 2018 12;320:2354-2364; Brown EE et al. Circ Genom Precis Med. 2020 Dec;13(6):e003082). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |