Submissions for variant NM_001267550.2(TTN):c.64453C>T (p.Arg21485Ter)

dbSNP: rs768345594

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209173	SCV000189692	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	RCV001059746	SCV001224390	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-04-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as 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: 223315). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 25589632, 29773157; Invitae). This variant is present in population databases (rs768345594, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg21485*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
GeneDx	RCV002291595	SCV002584327	pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing	Identified in patients with DCM referred for genetic testing at GeneDx and in published literature (Roberts et al., 2015; Anderson et al., 2020; Mazzarotto et al., 2020); Identified in an individual with alcoholic cardiomyopathy in the published literature (Ware et al., 2018). The R21485X variant was identified in two siblings also with alcoholic cardiomyopathy and a history of prolonged heavy alcohol consumption; however two family members who were also heterozygous for the R21485X variant but without a history of regular alcohol intake were clinically unaffected. Lastly, two family members with a history of heavy alcohol consumption but did not harbor the R21485X variant were also clinically unaffected.; 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: 32998006, 25589632, 31983221, 22335739, 29773157)
Ambry Genetics	RCV002347817	SCV002620721	likely pathogenic	Cardiovascular phenotype	2023-03-27	criteria provided, single submitter	clinical testing	The p.R12420* variant (also known as c.37258C>T), located in coding exon 136 of the TTN gene, results from a C to T substitution at nucleotide position 37258. This changes the amino acid from an arginine to a stop codon within coding exon 136. 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 alteration has been reported (noted as NM_001267550.1: p.R21485*(c.64453C>T)) in association with dilated cardiomyopathy (DCM) (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302). 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.
Clinical Genomics Laboratory, Stanford Medicine	RCV004020568	SCV005016645	likely pathogenic	Dilated cardiomyopathy 1G	2021-07-02	criteria provided, single submitter	clinical testing	•The p.Arg21485* variant in the TTNgene has been previously reported in at least 2 unrelated individuals with dilated cardiomyopathy and co-segregated with disease in at least 2 affected relatives from 1 family (Mazzarrato et al., 2020; Roberts et al., 2015; Ware et al., 2018). •This variant has been identified in 4/34,206 Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). •The p.Arg21485* variant leads to a premature termination; however, premature termination at this location of the gene may not undergo nonsense-mediated decay, increasing the likelihood of an expressed protein.•The p.Arg21485* variant is located in the A-band of the titin protein. Other pathogenic and likely pathogenic truncating variants have been described in the A-band.•These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg21485* variant as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PVS1_strong; PS4_supporting; PM2]
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525901	SCV005039518	pathogenic	Primary familial dilated cardiomyopathy	2024-03-29	criteria provided, single submitter	clinical testing	Variant summary: TTN c.56749C>T (p.Arg18917X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Nonsense, frameshift, and canonical splice-site variants in TTN are strongly associated with DCM when they affect exons encoding for the A-band region (PMIDs: 22335739, 24503780) and/or exons constitutively expressed (proportion spliced in [PSI]>0.9) in the primary cardiac isoforms (PMIDs: 25589632, 31216868, 32964742, 27869827), which is the case for this variant (located in the A band in an exon with PSI score of 100%). The variant allele was found at a frequency of 2e-05 in 246988 control chromosomes (gnomAD). c.56749C>T has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy, but was also found in unaffected individuals, consistent with a reduced penetrance (e.g. Roberts_2015, Ware_2018, Mazzarotto_2020, McGurk_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 223315). Based on the evidence outlined above, the variant was classified as pathogenic.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004020568	SCV005374927	pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing