ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.48283C>T (p.Arg16095Ter)

gnomAD frequency: 0.00001  dbSNP: rs374140736
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184218 SCV000236840 pathogenic not provided 2022-04-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 26688388, 32039858, 30471092, 21520333, 32528171, 34088380, 23975875, 23418287, 22335739, 25589632)
Ambry Genetics RCV000621940 SCV000737091 pathogenic Cardiovascular phenotype 2022-07-18 criteria provided, single submitter clinical testing The p.R7030* pathogenic mutation (also known as c.21088C>T), located in coding exon 84 of the TTN gene, results from a C to T substitution at nucleotide position 21088. This changes the amino acid from an arginine to a stop codon within coding exon 84 in the A-band region of the N2-B isoform of the titin protein. This variant (reported as c.40579C>T or p.R13527*) segregated with disease in three individuals in a family with dilated cardiomyopathy (DCM) (Norton N et al. Circ Cardiovasc Genet 2013 Apr; 6(2):144-53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Blueprint Genetics RCV000184218 SCV000927899 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000796818 SCV000936346 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-10-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg16095*) 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 (rs374140736, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 21520333, 23418287). It has also been observed to segregate with disease in related individuals. This variant is also known as c.40579C>T (Arg13527stop). ClinVar contains an entry for this variant (Variation ID: 202371). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256709 SCV001433112 pathogenic Dilated cardiomyopathy 1A 2020-01-07 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV004596103 SCV005091005 pathogenic Dilated cardiomyopathy 1G 2023-07-26 criteria provided, single submitter clinical testing PVS1, PS4, PM2, PP5 - ClinVar contains an entry for this variant (Variation ID: 202371). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are presented in patients affected with dilated cardiomyopathy (PMID: 25589632).
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere RCV004596103 SCV005375164 likely pathogenic Dilated cardiomyopathy 1G 2024-01-06 no assertion criteria provided clinical testing

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