Submissions for variant NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter)

gnomAD frequency: 0.00004  dbSNP: rs574660186

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000157564	SCV000189693	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.
GeneDx	RCV000255593	SCV000322336	pathogenic	not provided	2019-10-14	criteria provided, single submitter	clinical testing	Reported in association with DCM (Herman et al., 2012); Reported in ClinVar as a pathogenic and likely pathogenic variant (ClinVar Variant ID# 180573; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 25589632, 22335739, 27437901, 27625338, 25326635, 33534821)
Eurofins Ntd Llc (ga)	RCV000255593	SCV000338691	likely pathogenic	not provided	2018-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000684782	SCV000642456	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg22499*) 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 (rs574660186, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 22335739, 34935411). This variant is also known as c.62572C>T, p.Arg20858X. ClinVar contains an entry for this variant (Variation ID: 180573). 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.
Baylor Genetics	RCV000680139	SCV000807583	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	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found twice in our laboratory: heterozygous (maternally inherited) in a 12-year-old female with dilated cardiomyopathy and paternal family history of dilated cardiomyopathy (who also carried a paternally inherited likely pathogenic variant in BAG3); in trans with a missense variant in a 14-year-old female with global delays, epilepsy, scoliosis, clubbed digits, constipation (who also carried a de novo pathogenic variant in KCNT1).
Blueprint Genetics	RCV000255593	SCV000928048	pathogenic	not provided	2018-11-13	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000255593	SCV001879686	pathogenic	not provided	2020-12-23	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant occurs in the A-band of the TTN gene, and is a nonsense variant in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). Truncating variants in TTN occur significantly more often in the A-band of cardiomyopathy patients, and in the M-band of muscular dystrophy patients, compared to the general population (PMID: 255289632). Nonsense and other truncating variants in TTN have been reported in patients with dominant cardiomyopathy, dominant tibial muscular dystrophy, recessive salih myopathy, recessive limb-girdle muscular dystrophy, and recessive centronuclear myopathy (OMIM# 188840). However, these types of variants have also been found in healthy individuals (PMID: 25589632). This variant has been identified in at least one individual with dilated cardiomyopathy (DCM) (PMID: 22335739, 25589632).
Revvity Omics, Revvity	RCV000255593	SCV002022473	likely pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354385	SCV002620904	pathogenic	Cardiovascular phenotype	2023-01-06	criteria provided, single submitter	clinical testing	The p.R13434* pathogenic mutation (also known as c.40300C>T), located in coding exon 146 of the TTN gene, results from a C to T substitution at nucleotide position 40300. This changes the amino acid from an arginine to a stop codon within coding exon 146. 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 noted as c.62572C>T and c.67495C>T) has been reported in subjects with 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). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000680139	SCV002792378	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
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586577	SCV005038529	pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PVS1+PM2+PP1