ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.43600C>T (p.Gln14534Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504499
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000155637 SCV000205345 likely pathogenic Primary dilated cardiomyopathy 2015-07-30 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV004700482 SCV000236832 likely pathogenic not provided 2024-04-29 criteria provided, single submitter clinical testing Has been observed in at least one individual from a cohort of patients with nonischemic dilated cardiomyopathy (PMID: 32998006); Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies. (PMID: 27625338, 27869827); This variant is associated with the following publications: (PMID: 27625338, 27869827, 32998006)
Labcorp Genetics (formerly Invitae), Labcorp RCV001216159 SCV001387939 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-11-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln14534*) 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 (rs727504499, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 32998006). ClinVar contains an entry for this variant (Variation ID: 178865). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002399552 SCV002707691 likely pathogenic Cardiovascular phenotype 2023-09-25 criteria provided, single submitter clinical testing The p.Q5469* variant (also known as c.16405C>T), located in coding exon 63 of the TTN gene, results from a C to T substitution at nucleotide position 16405. This changes the amino acid from a glutamine to a stop codon within coding exon 63. This exon is located in the I-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 (referred to as p.Gln14534Ter, c.43600C>T) has been detected in a dilated cardiomyopathy (DCM) cohort; however, details were limited (Anderson JL et al. Am J Cardiol. 2020 12;137:97-102). 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 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.

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