Submissions for variant NM_001267550.2(TTN):c.53206C>T (p.Arg17736Ter)

dbSNP: rs571702144

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376964	SCV001574173	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg17736*) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with atrial fibrillation, dilated cardiomyopathy, and/or sudden infant death syndrome (PMID: 25163546, 28045975, 29544605, 30535219, 31983221, 33996946, 34495297, 35653365, 37652022). This variant is also known as c.C26587T (p.R8863X) and c.26011C>T (p.Arg8671*). ClinVar contains an entry for this variant (Variation ID: 1066067). 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	RCV002051941	SCV002319087	likely pathogenic	not provided	2024-06-03	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 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); Reported in association with DCM, early-onset atrial fibrillation, sudden infant death syndrome (SIDS), and skeletal muscle disease in published literature (PMID: 30535219, 25163546, 28045975, 29544605, 31983221, 32039858, 34495297, 35653365); This variant is associated with the following publications: (PMID: 31983221, 32039858, 29544605, 25163546, 28045975, 34495297, 35653365, 22335739, 30535219, Chmielewski_2024(Article), 33996946)
Ambry Genetics	RCV002432058	SCV002744472	pathogenic	Cardiovascular phenotype	2024-09-12	criteria provided, single submitter	clinical testing	The p.R8671* pathogenic mutation (also known as c.26011C>T), located in coding exon 104 of the TTN gene, results from a C to T substitution at nucleotide position 26011. This changes the amino acid from an arginine to a stop codon within coding exon 104. 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 (also referred to as p.R8863*, c.26587C>T and p.R17736*, c.53206C>T) has been detected in dilated cardiomyopathy (DCM), sudden infant death and early onset atrial fibrillation cohorts, and has been reported to segregate with DCM in a family (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a; Franaszczyk M et al. PLoS ONE, 2017 Jan;12:e0169007; Tester DJ et al. J. Am. Coll. Cardiol., 2018 03;71:1217-1227; Choi SH et al. JAMA, 2018 12;320:2354-2364). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004764965	SCV005375183	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing