Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV000118752 | SCV000153257 | uncertain significance | not provided | 2014-02-03 | criteria provided, single submitter | clinical testing | |
Cardiovascular Biomedical Research Unit, |
RCV000209291 | SCV000189681 | uncertain significance | Primary dilated cardiomyopathy | 2014-10-08 | criteria provided, single submitter | research | This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. |
Gene |
RCV000118752 | SCV000490938 | likely pathogenic | not provided | 2015-12-24 | criteria provided, single submitter | clinical testing | The c.35635G>C (V11879L, aka c.32854 G>C or V10952L) variant in the TTN gene has been published previouslyin one individual with dilated cardiomyopathy (DCM) (Herman et al., 2012). This variant has also been reported inassociation with autosomal recessive centronuclear myopathy (CNM) (Ceyhan-Birsoy et al., 2013; Brownstein et al.,2014). The c.32854 G>C variant has been identified at GeneDx in one family with autosomal recessive CNM whoalso harbor a TTN canonical splice site variant in trans. The c.35635G>C variant was not associated with anincreased risk of DCM in family members who only harbored this variant. This variant is located in the I-band regionof titin and a splicing assay demonstrated that the c.35635 G>C variant results in skipping of exon 168 leading toeither a truncated protein product or complete absence of protein from this allele due to nonsense mediated mRNAdecay (Ceyhan-Birsoy et al., 2013). Other splice site variants have been reported in the Human Gene MutationDatabase in association with autosomal recessive CNM and autosomal dominant DCM (Stenson et al., 2014).Furthermore, the NHLBI Exome Sequencing Project reports c.32854 G>C was not observed in approximately 5,900individuals of European and African American backgrounds, indicating it is not a common benign variant in thesepopulations. However, other truncating TTN variants have been reported in approximately 3% of control alleles(Herman et al., 2012). The contribution of the c.35635 G>C variant to the pathogenesis of autosomal dominant DCMis unclear. Therefore, this variant is likely pathogenic. |
Invitae | RCV000525548 | SCV000643122 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-11-03 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 13520 of the TTN protein (p.Val13520Leu). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive centronuclear myopathy or limb-girdle muscular dystrophy and/or dilated cardiomyopathy (PMID: 22335739, 23975875, 30681174). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.35635G>C or c.32854G>C. ClinVar contains an entry for this variant (Variation ID: 130666). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 219, but is expected to preserve the integrity of the reading-frame (PMID: 23975875). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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). For these reasons, this variant has been classified as Pathogenic. |
Athena Diagnostics Inc | RCV000118752 | SCV001477138 | uncertain significance | not provided | 2020-03-10 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000118752 | SCV001747286 | likely pathogenic | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | TTN: PM2, PM3, PP3, PS3:Supporting, PS4:Supporting |
Ai |
RCV000118752 | SCV002501218 | uncertain significance | not provided | 2022-01-26 | criteria provided, single submitter | clinical testing | |
Genomics England Pilot Project, |
RCV001542652 | SCV001760068 | likely pathogenic | Dilated cardiomyopathy 1G | no assertion criteria provided | clinical testing | ||
Genome |
RCV003235044 | SCV003935000 | not provided | Cardiomyopathy | no assertion provided | phenotyping only | Variant classified as pathogenic on 12/26/2012 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. |