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

gnomAD frequency: 0.00001  dbSNP: rs727505350

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2024-06-07	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; 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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25163546, 27813223, 29447731, 33874732, 31112426, 35177841, 37178278, 31691645, 36264615, 27625338, 27869827)
Eurofins Ntd Llc (ga)	RCV000725890	SCV000340274	uncertain significance	not provided	2018-08-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620569	SCV000735745	pathogenic	Cardiovascular phenotype	2023-05-01	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 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 (also 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 (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 DCM in a large family (Jansweijer JA et al. Eur. J. Heart Fail., 2017 04;19:512-521). 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 Jan;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705371	SCV000834363	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg14967*) 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 individuals with autosomal dominant dilated cardiomyopathy and/or noncompaction cardiomyopathy (PMID: 27813223, 29447731, 31112426, 33874732, 36264615; Invitae). This variant is also known as c.18280C>T (p.Arg6094*) and c.37195C>T (p.Arg12399*). ClinVar contains an entry for this variant (Variation ID: 180102). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). For these reasons, this variant has been classified as Pathogenic.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004764904	SCV005375151	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing