Submissions for variant NM_001267550.2(TTN):c.75328C>T (p.Arg25110Ter)

dbSNP: rs794729382

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184390	SCV000237015	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	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); Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22335739, 35177841, 33432171)
Invitae	RCV000532259	SCV000642463	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg25110*) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 202521). 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.
Ambry Genetics	RCV002336479	SCV002637872	likely pathogenic	Cardiovascular phenotype	2022-10-07	criteria provided, single submitter	clinical testing	The p.R16045* variant (also known as c.48133C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 48133. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 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 Jan;49:46-53). As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002485237	SCV002777901	likely 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	2021-11-18	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000184390	SCV000924983	likely pathogenic	not provided	2017-09-11	no assertion criteria provided	provider interpretation	Given that this is a rare, truncating variant in the A-band of TTN, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN variants are the most common cause of idiopathic dilated cardiomyopathy. Variant type: Truncating variant in the A-band. TTN truncating variants are seen in 13-30% of people with DCM and are thought to confer pathogenesis in a dominant-negative fashion (Herman et al 2012, Roberts et al 2015). There is strong evidence implicating them in the pathogenesis of DCM, though it remains unclear whether they are confer risk in a Mendelian or multifactorial fashion (Watkins et al 2015). Furthermore, each individual TTN variant must be evaluated carefully for potential pathogenicity given the presence of truncating TTN variants in 1-3% of the general population (Herman et al 2012, Roberts et al 2015) and the failure of some TTN truncating variants to segregate in DCM families (Norton et al 2013). TTN truncating variants located in the A-band and in exons frequently included in the cardiac isoforms N2B and N2BA are enriched in DCM patients versus controls (Roberts et al 2015). However, it is notable that when focusing these variants (A-band, frequently included N2B, N2BA), 15% of DCM cases and 1% of a normal sample have such variants (Roberts et al 2015). Roberts et al (2015) estimated that when such a variant is found in a proband there is a 93% chance it is disease-causing. Review of the p.Arg25510* truncating variant in cardiodb.org: The genomic coordinates for this variant are chr2: 179435531 (hg19). Per the TTN tool at cardiodb.org, LRG exon number is 326 (this is a meta exon number system created to include all TTN exons and preferred in reporting variants), N2BA transcript is 276. It is located in the A-band and is 100% spliced in to cardiac isoforms. Another variant in the same exon has previously been reported in more than 50 cases of DCM. Total number of cases (not including our patient): at least 1: -ClinVar: present -Classified as: likely pathogenic -Number of individuals: unknown -Submitted by: GeneDx -Last reviewed: March 2017 -Case data: There is no published literature available to review. Prevalence in the general population: Per varsome.com it is not present in gnomAD, which has >140,000 samples. Median coverage in exome samples is 93.9x and in genome samples is 34.3x.