ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.44899C>T (p.Arg14967Ter) (rs727505350)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156906 SCV000206627 uncertain significance not specified 2014-11-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg12399X variant in TTN has not been previously reported in individuals with cardiomyopa thy or in large population studies. This nonsense variant leads to a premature t ermination codon at position 12399, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly asso ciated with DCM, particularly if they are located in the exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014). Variants in the I-band, w here the p.Arg12399X variant is located, occur at a greater frequency in control s than in individuals with DCM (Pugh 2014). This decreases the likelihood, but d oes not rule out that this variant has a role in disease. In summary, while the predicted impact of this variant provides some suspicion for a pathogenic role, the clinical significance of the p.Arg12399X variant is uncertain.
GeneDx RCV000725890 SCV000236837 pathogenic not provided 2021-05-13 criteria provided, single submitter clinical testing Reported in ClinVar (ClinVar Variant ID# 180102; Landrum et al., 2016); Not observed at 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 one of the constitutive exons in the I-band region. Studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are significantly associated with DCM (Deo, 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 25163546, 27813223, 29447731)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725890 SCV000340274 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620569 SCV000735745 pathogenic Cardiovascular phenotype 2020-04-14 criteria provided, single submitter clinical testing The p.R5902* pathogenic mutation (also known as c.17704C>T), located in coding exon 70 of the TTN gene, results from a C to T substitution at nucleotide position 17704. This changes the amino acid from an arginine to a stop codon within coding exon 70. This exon is located downstream of the Cronos internal promoter, in the I-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percentage spliced in or PSI 100%). This alteration, referred to as c.18280C>T (p.R6094*) and c.37195C>T (p.R12399), has been detected in dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC) cohorts, albeit with limited clinical detail (Haas J et al. Eur. Heart J. 2015 May;36:1123-35a; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722). This variant (referred to as c.44899C>T p.R14967*) has also been reported to segregate with disease in a large family (Jansweijer JA et al. Eur. J. Heart Fail., 2017 04;19:512-521). 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 Jan;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000705371 SCV000834363 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-12-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg14967*). 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 (ExAC no frequency). This variant has been reported to segregate with disease in a family affected with dilated cardiomyopathy (PMID: 27813223). This variant is also known as c.18280C>T (p.Arg6094*) in the literature. ClinVar contains an entry for this variant (Variation ID: 180102). This variant identified in the TTN gene is located in the I band of the resulting protein (PMID: 25589632) In summary, although this is a novel truncating variant, truncating variants in this region of the TTN gene have been shown to be highly prevalent in the TTN gene in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating mutations in this region have also been reported to cause autosomal recessive congenital myopathy (PMID: 23975875). Therefore without additional functional and/or genetic data, this variant has been classified as a Variant of Uncertain Significance.

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