Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001379762 | SCV001577626 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Pro34954Hisfs*5) 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 premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 32998006). ClinVar contains an entry for this variant (Variation ID: 1068262). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). 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. |
| Prevention |
RCV003394020 | SCV004119666 | likely pathogenic | TTN-related condition | 2022-12-20 | criteria provided, single submitter | clinical testing | The TTN c.104861_104876del16 variant is predicted to result in a frameshift and premature protein termination (p.Pro34954Hisfs*5). This variant has been reported in an individual with dilated cardiomyopathy (Table 2, Anderson et al. 2020. PubMed ID: 32998006). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant occurs in exon 359 which is located in the M-band region of the TTN protein. Exons 359-364 (Mex1-Mex6) have historically been found to harbor a significant number of pathogenic variants for TTN-related autosomal dominant and recessive muscle disorders (Hackman et al. 2002. PMID: 12145747; Evilä et al. 2014. PMID: 24395473). Other nearby protein truncating variants in this exon (eg. p.Gln34757*, p.Arg34805*, p.Glu34818T*, p.Lys35181*) have been reported in individuals with dilated cardiomyopathy or early onset atrial fibrillation (Mehaney. 2021. PubMed ID: 34036930; Marschall. 2019. PubMed ID: 31737537; Chalazan. 2021. PubMed ID: 33950154; Wang. 2022. PubMed ID: 34350506). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts A.M. et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). Many cases of recessive congenital TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). In summary, the c.104861_104876del16 (p.Pro34954Hisfs*5) variant is likely pathogenic for autosomal dominant and recessive TTN-related disorders. |