Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001378033 | SCV001575515 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-09-01 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg17223*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal dominant and autosomal recessive TTN-related conditions (PMID: 25163546, 32778822; Invitae). This variant is also known as c.C25048T, p.R8350X. ClinVar contains an entry for this variant (Variation ID: 1066907). 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. |
Gene |
RCV002291754 | SCV002584436 | pathogenic | not provided | 2024-01-03 | criteria provided, single submitter | clinical testing | 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 (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34135346, 36264615, 25163546, 32778822, 22335739) |
Ambry Genetics | RCV002432062 | SCV002731522 | likely pathogenic | Cardiovascular phenotype | 2023-12-26 | criteria provided, single submitter | clinical testing | The p.R8158* variant (also known as c.24472C>T), located in coding exon 99 of the TTN gene, results from a C to T substitution at nucleotide position 24472. This changes the amino acid from an arginine to a stop codon within coding exon 99. 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic. |
Rady Children's Institute for Genomic Medicine, |
RCV004545824 | SCV004046425 | likely pathogenic | TTN-related disorder | criteria provided, single submitter | clinical testing | This variant is also known as c.25048C>T (p.Arg8350Term) in an alternate transcript NM_133437 (PMID: 25163546). This nonsense variant found in exon 273 of TTN is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in autosomal dominant DCM, autosomal recessive titinopathy and also in an asymptomatic elderly individual (PMID: 25163546, 32778822, 34135346). The c.51667C>T variant is located in the A-band of TTN (PMID: 25589632). Loss of function variants in the TTN gene have been reported in multiple databases, including the Human Gene Mutation Database and ClinVar, in association with cardiomyopathy. Additionally, a majority of these reported variants are located in the A-band region of TTN (PMID: 22335739). The c.51667C>T (p.Arg17223Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/248152) and thus is presumed to be rare. Based on the available evidence, the c.51667C>T (p.Arg17223Ter) variant is classified as Likely Pathogenic. | |
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, |
RCV004764966 | SCV005375179 | likely pathogenic | Dilated cardiomyopathy 1G | 2024-01-06 | no assertion criteria provided | clinical testing |