ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.76115dup (p.Asn25372fs) (rs774604740)

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Total submissions: 5
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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 RCV000209488 SCV000189787 likely pathogenic Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research This TTN truncating variant (TTNtv) was identified in two individuals 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.
Invitae RCV000469186 SCV000542936 likely pathogenic Dilated cardiomyopathy 1G 2016-08-30 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 326 of the TTN mRNA (c.76115dupA), causing a frameshift at codon 25372. This creates a premature translational stop signal (p.Asn25372Lysfs*5) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. This particular variant was reported in an individual with dilated cardiomyopathy (PMID: 25589632). Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 223383). For these reasons, this variant has been classified as Likely Pathogenic.
GeneDx RCV000483913 SCV000567335 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing Identified in patients with DCM referred for genetic testing at GeneDx and in the literature (Roberts et al., 2015; Marston et al., 2015; Vikhorev et al., 2017); also denoted as c.76115dupA (p.Asn25372fs), p.N16499Kfs*5, and c.68408_68411del(A)4ins(A)5 (p.N22804K fs*5) due to the use of alternate transcripts and/or nomenclature; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift 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: 29093449, 25589632, 26406308)
Illumina Clinical Services Laboratory,Illumina RCV000779287 SCV000915869 uncertain significance TTN-Related Disorders 2017-08-16 criteria provided, single submitter clinical testing The TTN c.68411dupA (p.Asn22804LysfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. This variant has been reported in one study and is found in a heterozygous state in two individuals with dilated cardiomyopathy (Roberts et al. 2015). This variant has not been described in the literature in association with hereditary myopathy with early respiratory failure, hypertrophic cardiomyopathy, recessive limb-girdle muscular dystrophy, Salih myopathy, or Udd distal myopathy. The p.Asn22804LysfsTer5 was absent from 308 controls. The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Due to the limited evidence and potential impact of frameshift variants, the p.Asn22804LysfsTer5 variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001378109 SCV001575605 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-03-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Asn25372Lysfs*5). 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 ExAC database. This frameshift change has been observed in individual(s) with dilated cardiomyopathy (PMID: 29093449, 25589632, 26406308). 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.

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