Submissions for variant NM_001267550.2(TTN):c.89900_89903del (p.Asn29967fs)

dbSNP: rs869312081

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	RCV000209065	SCV000189703	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	RCV000521895	SCV000617538	likely pathogenic	not provided	2018-02-06	criteria provided, single submitter	clinical testing	The c.84977_84980delATTA likely pathogenic variant in the TTN gene has been reported in association with DCM (Herman et al., 2012); however, functional studies and segregation information were not provided. This variant causes a shift in reading frame starting at codon asparagine 28326, changing it to a methionine, and creating a premature stop codon at position 27 of the new reading frame, denoted p.Asn28326MetfsX27. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.84977_84980delATTA is 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). Furthermore, the c.84977_84980delATTA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Blueprint Genetics	RCV000521895	SCV000927539	likely pathogenic	not provided	2018-02-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045476	SCV001209329	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn29967Metfs*27) 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 individual(s) with clinical features of dilated cardiomyopathy, myopathy or muscular dystrophy (PMID: 22335739, 25589632, 29792937). This variant is also known as c.84977_84980delATTA. ClinVar contains an entry for this variant (Variation ID: 223324). 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	RCV002363045	SCV002660026	pathogenic	Cardiovascular phenotype	2020-10-22	criteria provided, single submitter	clinical testing	The c.62705_62708delATTA pathogenic mutation, located in coding exon 162 of the TTN gene, results from a deletion of 4 nucleotides at nucleotide positions 62705 to 62708, causing a translational frameshift with a predicted alternate stop codon (p.N20902Mfs*27). 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 (also referred to as c.84977_84980delATTA and c.89900_89903delATTA) has been detected in individuals reported to have 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), and in a myopathy/muscular dystrophies cohort for which clinical details were limited (Zenagui R et al. J Mol Diagn, 2018 07;20:533-549). 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	RCV002500672	SCV002810448	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	2021-07-20	criteria provided, single submitter	clinical testing
deCODE genetics, Amgen	RCV003485563	SCV004022137	likely pathogenic	Dilated cardiomyopathy 1G	2023-07-21	no assertion criteria provided	research	The variant NM_001267550.2:c.89900_89903del (chr2:178552996) in TTN was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.