ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.75250C>T (p.Arg25084Ter)

dbSNP: rs794729286
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184262 SCV000236884 pathogenic not provided 2013-03-27 criteria provided, single submitter clinical testing p.Arg23443Stop (CGA>TGA): c.70327 C>T in exon 276 of the TTN gene (NM_001256850.1). The Arg23443Stop mutation in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg23443Stop is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, Arg23443Stop is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, Arg23443Stop in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
Blueprint Genetics RCV000184262 SCV000927360 likely pathogenic not provided 2017-07-28 criteria provided, single submitter clinical testing
Invitae RCV001377801 SCV001575226 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-11-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg25084*) 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 individual(s) with unspecified cardiomyopathy (PMID: 30847666). This variant is also known as c.67546C>T (p.(Arg22516*). ClinVar contains an entry for this variant (Variation ID: 202406). 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.
Ambry Genetics RCV002336473 SCV002637781 likely pathogenic Cardiovascular phenotype 2021-02-20 criteria provided, single submitter clinical testing The p.R16019* variant (also known as c.48055C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 48055. 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 variant (referred to as NM_133378.4:c.67546C>T, p.R22516*) has been detected in an individual with unknown cardiomyopathy; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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). As such, this alteration is classified as likely pathogenic.

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