Submissions for variant NM_001267550.2(TTN):c.92683C>T (p.Arg30895Ter)

dbSNP: rs869312065

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209537	SCV000189673	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853336	SCV002257501	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg30895*) 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 dilated cardiomyopathy or Wolff–Parkinson–White syndrome (PMID: 25589632, 31983221, 32233023; Invitae). This variant is also known as p.Arg21955*. ClinVar contains an entry for this variant (Variation ID: 223300). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000209537	SCV004848218	likely pathogenic	Primary dilated cardiomyopathy	2018-07-25	criteria provided, single submitter	clinical testing	The p.Arg28327X variant in TTN has been reported in 1 individual with dilated cardiomyopathy (Roberts 2015) and 1 individual with Wolff-Parkinson-White syndrome (ClinVar ID# 223300), and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 28327, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). This variant is located in A-band in the highly expressed exon 288. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg28327X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
Ambry Genetics	RCV004678645	SCV005180548	likely pathogenic	Cardiovascular phenotype	2024-05-13	criteria provided, single submitter	clinical testing	The p.R21830* variant (also known as c.65488C>T), located in coding exon 166 of the TTN gene, results from a C to T substitution at nucleotide position 65488. This changes the amino acid from an arginine to a stop codon within coding exon 166. 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, noted as c.92683C>T or c.65863C>T has been reported in association with dilated cardiomyopathy (DCM) and Wolff-Parkinson-White syndrome (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Coban-Akdemir ZH et al. Am J Med Genet A, 2020 Jun;182:1387-1399). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001594385	SCV005400299	pathogenic	Dilated cardiomyopathy 1G	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature termination codon are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes). (SP) 0600 - Variant is located in the A-band and the exon has a PSI score of 100 (PMID: 25589632). (I) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in five unrelated individuals with DCM, including one who also has variants of uncertain significance in other cardiac genes (ClinVar, personal communication; PMIDs: 25589632, 31983221, 34011823). It has also been reported in an individual with sudden cardiac arrest in ventricular fibrillation and an individual with Wolff-Parkinson-White syndrome (ClinVar, personal communication; PMID: 32233023). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656220	SCV000678414	likely pathogenic	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome
KTest Genetics, KTest	RCV001594385	SCV001499990	pathogenic	Dilated cardiomyopathy 1G		no assertion criteria provided	clinical testing
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV001594385	SCV005375060	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing