ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.60681dup (p.Lys20228Ter)

gnomAD frequency: 0.00001  dbSNP: rs797044692
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000294518 SCV000331698 likely pathogenic not provided 2014-10-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000823705 SCV000964574 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2025-01-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys20228*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 33874732). ClinVar contains an entry for this variant (Variation ID: 195920). 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.
GeneDx RCV000294518 SCV002074061 pathogenic not provided 2023-12-14 criteria provided, single submitter clinical testing 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; Not observed at significant frequency in large population cohorts (gnomAD); Reported in a patient with peripartum cardiomyopathy (PMID: 33874732); This variant is associated with the following publications: (PMID: 25589632, 23975875, 27535533, 33874732, 22335739)
AiLife Diagnostics, AiLife Diagnostics RCV000294518 SCV002502740 likely pathogenic not provided 2021-09-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV002321701 SCV002607114 likely pathogenic Cardiovascular phenotype 2023-07-11 criteria provided, single submitter clinical testing The c.33486dupT variant, located in coding exon 131 of the TTN gene, results from a duplication of T at nucleotide position 33486, causing a translational frameshift with a predicted alternate stop codon (p.K11163*). 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 (described as NM_001267550.1:c.60681dupT) has been reported in a peripartum cardiomyopathy cohort; however, clinical details were limited (Goli R et al. Circulation, 2021 05;143:1852-1862). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
Fulgent Genetics, Fulgent Genetics RCV002478580 SCV002786561 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-12-20 criteria provided, single submitter clinical testing

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