ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.45322C>T (p.Arg15108Ter)

gnomAD frequency: 0.00001  dbSNP: rs1060500405
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000457096 SCV000542302 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-03-25 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, 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: 404655). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 26084686, 30858397). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg15108*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Blueprint Genetics RCV000788734 SCV000927955 likely pathogenic not provided 2018-09-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV004022552 SCV005020864 likely pathogenic Cardiovascular phenotype 2023-11-03 criteria provided, single submitter clinical testing The p.R6043* variant (also known as c.18127C>T), located in coding exon 72 of the TTN gene, results from a C to T substitution at nucleotide position 18127. This changes the amino acid from an arginine to a stop codon within coding exon 72. This exon is located in the I-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 NM_001267550:c.45322C>T, p.Arg15108*) has been detected in an individual from a dilated cardiomyopathy cohort (Akinrinade O et al. Eur Heart J, 2015 Sep;36:2327-37). 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 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 majority of available evidence to date, this variant is likely to be pathogenic.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere RCV004764926 SCV005375152 likely pathogenic Dilated cardiomyopathy 1G 2024-01-06 no assertion criteria provided clinical testing

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