ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter) (rs574660186)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000157564 SCV000189693 likely pathogenic 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.
Blueprint Genetics RCV000157564 SCV000207310 likely pathogenic Primary dilated cardiomyopathy 2015-05-06 criteria provided, single submitter clinical testing
GeneDx RCV000255593 SCV000322336 pathogenic not provided 2019-10-14 criteria provided, single submitter clinical testing Reported in association with DCM (Herman et al., 2012); Reported in ClinVar as a pathogenic and likely pathogenic variant (ClinVar Variant ID# 180573; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 25589632, 22335739, 27437901, 27625338, 25326635, 33534821)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255593 SCV000338691 likely pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing
Invitae RCV000684782 SCV000642456 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-02-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 22499 (p.Arg22499*) of the TTN gene. It is expected to result in a disrupted protein product. This variant is found in the A-band of this gene. Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be pathogenic for the disease (PMID: 25589632). This particular variant has been observed in several individuals with dilated cardiomyopathy (PMID: 22335739, 25589632). ClinVar contains an entry for this variant (Variation ID: 180573). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000680139 SCV000807583 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Myopathy, early-onset, with fatal cardiomyopathy; Familial hypertrophic cardiomyopathy 9 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory: heterozygous (maternally inherited) in a 12-year-old female with dilated cardiomyopathy and paternal family history of dilated cardiomyopathy (who also carried a paternally inherited likely pathogenic variant in BAG3); in trans with a missense variant in a 14-year-old female with global delays, epilepsy, scoliosis, clubbed digits, constipation (who also carried a de novo pathogenic variant in KCNT1).
Blueprint Genetics RCV000255593 SCV000928048 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255593 SCV001879686 pathogenic not provided 2020-12-23 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant occurs in the A-band of the TTN gene, and is a nonsense variant in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). Truncating variants in TTN occur significantly more often in the A-band of cardiomyopathy patients, and in the M-band of muscular dystrophy patients, compared to the general population (PMID: 255289632). Nonsense and other truncating variants in TTN have been reported in patients with dominant cardiomyopathy, dominant tibial muscular dystrophy, recessive salih myopathy, recessive limb-girdle muscular dystrophy, and recessive centronuclear myopathy (OMIM# 188840). However, these types of variants have also been found in healthy individuals (PMID: 25589632). This variant has been identified in at least one individual with dilated cardiomyopathy (DCM) (PMID: 22335739, 25589632).

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