Submissions for variant NM_001267550.2(TTN):c.64999C>T (p.Arg21667Ter)

dbSNP: rs794729280

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184250	SCV000236872	pathogenic	not provided	2013-08-13	criteria provided, single submitter	clinical testing	p.Arg20026Stop (CGA>TGA): c.60076 C>T in exon 261 of the TTN gene (NM_001256850.1). The Arg20026Stop mutation in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Arg20026Stop is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, Arg20026Stop is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, Arg20026Stop was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Arg20026Stop in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
Invitae	RCV001203632	SCV001374805	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg21667*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of dilated cardiomyopathy (PMID: 32880476, 36264615; Invitae). ClinVar contains an entry for this variant (Variation ID: 202399). 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.
Ambry Genetics	RCV002345647	SCV002620441	likely pathogenic	Cardiovascular phenotype	2021-08-06	criteria provided, single submitter	clinical testing	The p.R12602* variant (also known as c.37804C>T), located in coding exon 138 of the TTN gene, results from a C to T substitution at nucleotide position 37804. This changes the amino acid from an arginine to a stop codon within coding exon 138. 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 (referred to as c.64999C>T, p.R21667*) has been detected in an individual from a dilated cardiomyopathy cohort (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). 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
Fulgent Genetics, Fulgent Genetics	RCV002485233	SCV002788975	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	2021-08-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003128233	SCV003804710	pathogenic	Dilated cardiomyopathy 1G	2023-01-17	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP