Submissions for variant NM_001267550.2(TTN):c.47494C>T (p.Arg15832Ter)

gnomAD frequency: 0.00001  dbSNP: rs751746401

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000250497	SCV000320505	pathogenic	Cardiovascular phenotype	2023-01-27	criteria provided, single submitter	clinical testing	The p.R6767* pathogenic mutation (also known as c.20299C>T), located in coding exon 80 of the TTN gene, results from a C to T substitution at nucleotide position 20299. This changes an amino acid from an arginine to a stop codon within coding exon 80. 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 (c.47494C>T, p.R15832X)) has been reported in early-onset atrial fibrillation and dilated cardiomyopathy cohorts (Choi SH et al. JAMA, 2018 12;320:2354-2364; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2019 Jul). 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 Jan;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464828	SCV000542243	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg15832*) 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 (rs751746401, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal dominant dilated cardiomyopathy and/or autosomal recessive centronuclear myopathy (PMID: 31317183, 32815318; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg6767*. ClinVar contains an entry for this variant (Variation ID: 264517). 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). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798759	SCV002042504	pathogenic	Cardiomyopathy	2020-06-25	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223202	SCV002501356	pathogenic	not provided	2021-08-18	criteria provided, single submitter	clinical testing
GeneDx	RCV002223202	SCV004170605	pathogenic	not provided	2023-11-14	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; Observed with an additional pathogenic variant in an individual with muscle weakness referred for genetic testing at GeneDx and testing of one parent suggests the variants are likely present on opposite alleles (in trans); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 35177841, 30535219, 31317183, 32815318, 34495297, 25589632, 23975875)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV005250043	SCV005900612	pathogenic	TTN-related disorder	2024-08-22	criteria provided, single submitter	clinical testing	This variant results in a c.20299C>T (p.Arg6767Ter) and a c.39790C>T (p.Arg13264Ter) change in alternate transcripts, respectively (NM_003319.4; NM_133378.4). This nonsense variant found in exon 253 of 363 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in TTN is an established mechanism of disease (PMID: 22335739). The c.47494C>T (p.Arg15832Ter) variant is located in the A-band region of TTN and is present in a constitutively expressed exon (percent spliced in or PSI 100%). Loss of function variants located in constitutively expressed exons (PSI >90%) have been reported to be enriched in dilated cardiomyopathy regardless of their position in the titin protein (PMID: 27869827). This variant has been previously reported in patients with dilated cardiomyopathy and atrial fibrillation (PMID: 31317183, 32815318, 30535219, 34495297, 36264615). This variant was also reported as a compound heterozygous variant in a patient with congenital myopathy (PMID: 38544359). The c.47494C>T (p.Arg15832Ter) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.0006% (9/1612382) and thus is presumed to be rare. Based on the available evidence, c.47494C>T (p.Arg15832Ter) is classified as Pathogenic.