ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.40558G>C (p.Val13520Leu) (rs587780488)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118752 SCV000153257 uncertain significance not provided 2014-02-03 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust 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.
GeneDx 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; Limb-girdle muscular dystrophy, type 2J 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 13520 of the TTN protein (p.Val13520Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant also falls at the last nucleotide of exon 219 of the TTN coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant is located in the I-band of the TTN gene (PMID: 25589632). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with limb girdle weakness and congestive heart failure (Invitae), it has also been reported in the compound heterozygous state in one individual affected with centronuclear myopathy (PMID: 23975875). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported in the heterozygous state in an individual affected with dilated cardiomyopathy (PMID: 22335739). ClinVar contains an entry for this variant (Variation ID: 130666). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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