ClinVar Miner

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

dbSNP: rs587780488
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Total submissions: 9
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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; 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
CeGaT Center for Human Genetics Tuebingen RCV000118752 SCV001747286 likely pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing TTN: PM2, PM3, PP3, PS3:Supporting, PS4:Supporting
AiLife Diagnostics, AiLife Diagnostics RCV000118752 SCV002501218 uncertain significance not provided 2022-01-26 criteria provided, single submitter clinical testing
Genomics England Pilot Project, Genomics England RCV001542652 SCV001760068 likely pathogenic Dilated cardiomyopathy 1G no assertion criteria provided clinical testing
GenomeConnect, ClinGen 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.

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