Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000799871 | SCV000939553 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-09-21 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg29609*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 645724). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256861 | SCV001433351 | pathogenic | Arrhythmogenic right ventricular dysplasia 1 | 2020-04-23 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002352352 | SCV002654961 | likely pathogenic | Cardiovascular phenotype | 2019-05-15 | criteria provided, single submitter | clinical testing | The p.R20544* variant (also known as c.61630C>T), located in coding exon 159 of the TTN gene, results from a C to T substitution at nucleotide position 61630. This changes the amino acid from an arginine to a stop codon within coding exon 159. 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. |
Gene |
RCV003320751 | SCV004025661 | likely pathogenic | not provided | 2023-02-07 | criteria provided, single submitter | clinical testing | Reported in a patient with DCM in published literature (Stava et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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 TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 22335739, 35653365) |