Submissions for variant NM_001267550.2(TTN):c.61876C>T (p.Arg20626Ter)

gnomAD frequency: 0.00006  dbSNP: rs72646846

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211745	SCV000064136	likely pathogenic	Primary dilated cardiomyopathy	2019-03-08	criteria provided, single submitter	clinical testing	The p.Arg18058X variant in TTN has been identified in >20 individuals with DCM and segregated with disease in 3 affected individuals from 3 families (Herman 2012, Merlo 2013, unpublished data from GeneDx, Ambry, Invitae, and LMM). It has also been identified in 6 individuals with centronuclear myopathy or who underwent genetic testing for neuromuscular disorders (Elahi 2018, EGL pers. comm., Invitae pers. comm.). This variant has been identified in 0.16% (17/10348) of Ashkenazi Jewish, 1/128284 European, and 1/35320 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although the frequency in the Ashkenazi Jewish population is higher than expected for a pathogenic variant based on the disease prevalence of DCM, a comparison of the prevalence of this variant in the gnomAD database to DCM patients (LMM data only) shows that it is statistically enriched in the patient population (OR=23.4, p<0.0001). This nonsense variant leads to a premature termination codon at position 18058, which is predicted to lead to a truncated or absent protein. TTN truncating variants located in exons that are highly expressed in the heart are strongly associated with autosomal dominant DCM, particularly if they are located in the A-band, where this variant is located (Herman 2012, Pugh 2014). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM based on the predicted loss of function impact, enrichment in affected individuals, and segregation studies. ACMG/AMP criteria applied: PVS1_Strong, PP1, PS4_Supporting.
GeneDx	RCV000184247	SCV000236869	likely pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	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); 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; Also known as p.(Arg18985*) due to the use of an alternate transcript; This variant is associated with the following publications: (PMID: 28798025, 30535219, 31660661, 24980681, 22335739, 30609409, 30536954, 25589632, 24503780, 31514951, 32160020, 32277046, 24119082, 35177841, 23975875)
Eurofins Ntd Llc (ga)	RCV000184247	SCV000339164	likely pathogenic	not provided	2016-02-18	criteria provided, single submitter	clinical testing
Invitae	RCV000642745	SCV000764432	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg20626*) 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 (rs72646846, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy and/or dilated cardiomyopathy (PMID: 22335739, 31660661). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.56953G>A, p.Arg18985*. ClinVar contains an entry for this variant (Variation ID: 47175). 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). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768966	SCV000900339	likely pathogenic	Cardiomyopathy	2018-07-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000184247	SCV001249867	pathogenic	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256787	SCV001433233	pathogenic	Dilated cardiomyopathy 1A	2019-01-15	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000211745	SCV001448746	pathogenic	Primary dilated cardiomyopathy	2018-11-29	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001537860	SCV001754795	likely pathogenic	Dilated cardiomyopathy 1G	2019-10-31	criteria provided, single submitter	clinical testing	The c.61876C>T (p.Arg20626Ter) variant in the TTN gene is predicted to introduce a premature translation termination codon and loss of normal protein function. This variant has been reported in two individuals with dilated cardiomyopathy (PMID: 22335739, 24119082). This variant is found in the A-band of TTN. Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000184247	SCV002021494	likely pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000184247	SCV002501912	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453326	SCV002612973	pathogenic	Cardiovascular phenotype	2023-08-10	criteria provided, single submitter	clinical testing	The p.R11561* pathogenic mutation (also known as c.34681C>T), located in coding exon 131 of the TTN gene, results from a C to T substitution at nucleotide position 34681. This changes the amino acid from an arginine to a stop codon within coding exon 131. 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 (also reported as c.56953C>T, p.R18985* in the NM_001256850.1 transcript) has been detected in individuals with dilated cardiomyopathy (DCM) and peripartum cardiomyopathy (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Merlo M et al. Clin Transl Sci, 2013 Dec;6:424-8; Naftali-Shani N et al Circulation. 2018;138(23):2721-2723), and has also been detected in a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). 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 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002477121	SCV002792529	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-10-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387740	SCV004099736	pathogenic	Primary familial dilated cardiomyopathy	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.54172C>T (p.Arg18058X) 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 forthis variant (A band). The variant allele was found at a frequency of 7.6e-05 in 248912 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (7.6e-05 vs 0.00039), allowing no conclusion about variant significance. c.54172C>T has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy (e.g. Herman_2012, Merlo_2013, Morales_2020, Enriquez_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 34315225, 22335739, 24119082, 32160020). Thirteen ClinVar submitters have assessed the variant since 2014: seven classified the variant as likely pathogenic, and six as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.