ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.73846C>T (p.Arg24616Ter)

gnomAD frequency: 0.00001  dbSNP: rs794729284
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184260 SCV000236882 pathogenic not provided 2023-01-20 criteria provided, single submitter clinical testing Identified in patients with DCM referred for genetic testing at GeneDx and in published literature (Corden et al., 2019; Mazzarotto et al., 2020) including one patient who underwent WES and the variant was de novo (Sea et al., 2020); 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 TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 22335739, 31980526, 31983221, 32901917, 31251381)
Invitae RCV000689621 SCV000817280 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-03-26 criteria provided, single submitter clinical testing 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. 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). ClinVar contains an entry for this variant (Variation ID: 202404). This premature translational stop signal has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 31251381, 31983221, 32901917; Invitae). This variant is present in population databases (rs794729284, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg24616*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics RCV002327001 SCV002633794 pathogenic Cardiovascular phenotype 2021-07-20 criteria provided, single submitter clinical testing The p.R15551* pathogenic mutation (also known as c.46651C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 46651. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 mutation (also referred to as c.73846C>T, Arg24616*) has been detected in two individuals from a dilated cardiomyopathy cohort, and in an individual from a genome sequencing cohort who did not have cardiomyopathy at the time of study; however, details were limited (Mazzarotto F et al. Circulation, 2020 02;141:387-398; Hou YC et al. Proc Natl Acad Sci U S A, 2020 02;117:3053-3062). 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 01;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV002485234 SCV002790432 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-11-01 criteria provided, single submitter clinical testing

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