ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.85267C>T (p.Arg28423Ter)

dbSNP: rs769664554
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001058528 SCV001223108 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg28423*) 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 (rs769664554, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 853671). 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.
PreventionGenetics, part of Exact Sciences RCV004735949 SCV005363226 likely pathogenic TTN-related disorder 2024-03-23 no assertion criteria provided clinical testing The TTN c.85267C>T variant is predicted to result in premature protein termination (p.Arg28423*). This variant was reported in five individuals with dilated cardiomyopathy (Table S IV, reported as chr2:178560865 in Bourfiss et al. 2022. PubMed ID: 36264615). The c.85267C>T variant is located in the A-band region of the TTN protein and several other premature stop variants in this exon have previously been reported to be pathogenic for recessive and dominant TTN-related disorders including dilated cardiomyopathy, centronuclear myopathy, and muscular dystrophy (Human Gene Mutation Database). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 95-100%; https://www.cardiodb.org/titin/titin_exon.php?id=327; Roberts A.M. et al. 2015. PMID: 25589632). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). Many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. In summary, the c.85267C>T, p.Arg28423* variant is pathogenic for both autosomal recessive and dominant TTN-related disorders. Of note, this variant is considered pathogenic for increased risk of TTN-related cardiac disorders, and also for autosomal recessive severe congenital titinopathies when in the presence of an additional loss-of-function TTN variant.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere RCV004764951 SCV005375027 likely pathogenic Dilated cardiomyopathy 1G 2024-01-06 no assertion criteria provided clinical testing

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