ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.92284_92288dup (p.Ser30763fs)

dbSNP: rs756367933
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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 RCV000208988 SCV000189761 uncertain significance 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.
GeneDx RCV000479332 SCV000569526 pathogenic not provided 2024-02-09 criteria provided, single submitter clinical testing 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 TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 35177841, 31112426, 34495297, 31691645, 25589632)
Labcorp Genetics (formerly Invitae), Labcorp RCV001379492 SCV001577304 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-11-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser30763Argfs*7) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs756367933, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 31112426, 34495297). ClinVar contains an entry for this variant (Variation ID: 223354). 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.
Ambry Genetics RCV002363048 SCV002659197 likely pathogenic Cardiovascular phenotype 2024-02-09 criteria provided, single submitter clinical testing The c.65089_65093dupAAAAG variant, located in coding exon 166 of the TTN gene, results from a duplication of AAAAG at nucleotide position 65089, causing a translational frameshift with a predicted alternate stop codon (p.S21698Rfs*7). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant has been reported in the Jackson Heart Study cohort with alternate nomenclature (NM_001267550.1:c.92284_92288dupAAAG p.S30763Rfs*7); however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.
Illumina Laboratory Services, Illumina RCV003389244 SCV004101322 likely pathogenic Dilated cardiomyopathy 1G 2023-06-13 criteria provided, single submitter clinical testing The TTN c.92284_92288dup (p.Ser30763ArgfsTer7) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is located in exon 339 of the meta transcript of titin within the A-band, which is highly expressed in cardiac tissue (PMID: 25589632). In a meta-analysis of TTN truncating variants in dilated cardiomyopathy (DCM) patients and controls, variants in this region were associated with a significantly increased risk of developing DCM (odds ratio 49.8) (PMID: 27869827). This variant has been reported in a heterozygous state in one individual with DCM (PMID: 31112426). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.92284_92288dup (p.Ser30763ArgfsTer7) variant is classified as likely pathogenic for dilated cardiomyopathy.

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