Submissions for variant NM_001267550.2(TTN):c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186fs)

gnomAD frequency: 0.00003  dbSNP: rs587780494

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118780	SCV000153341	pathogenic	Tibial muscular dystrophy	2013-09-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725865	SCV000340085	uncertain significance	not provided	2016-03-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000725865	SCV000567763	uncertain significance	not provided	2021-11-10	criteria provided, single submitter	clinical testing	Reported in association with early-onset atrial fibrillation in a whole-genome sequencing cohort (Choi et al., 2018); Reported in ClinVar (ClinVar Variant ID# 130679; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30535219)
Ambry Genetics	RCV000621565	SCV000737274	likely pathogenic	Cardiovascular phenotype	2023-05-09	criteria provided, single submitter	clinical testing	The c.6417_6418ins16 variant, located in coding exon 27 of the TTN gene, results from an insertion of 16 nucleotides (TGTAAGGAAACAGACA) at position 6417, causing a translational frameshift with a predicted alternate stop codon (p.K2140Cfs*15). This exon is located in the I-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 p.Lys2186fs) has been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA. 2018 12;320(22):2354-2364). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000795260	SCV000934709	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-12-02	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the TTN gene (p.Lys2186Cysfs*15). 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 ExAC database. This variant has been observed to segregate with dilated cardiomyopathy in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 130679). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000725865	SCV002502761	likely pathogenic	not provided	2021-10-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003389238	SCV004101340	likely pathogenic	Dilated cardiomyopathy 1G	2023-07-11	criteria provided, single submitter	clinical testing	The TTN c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186CysfsTer15) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is located in exon 29 of the meta transcript of titin within the I-band, which is highly expressed in cardiac tissue (PMID: 25589632). In a meta-analysis of TTN truncating variants in DCM patients and controls, variants in this region were associated with a significantly increased risk of developing DCM (odds ratio = 19.0) (PMID: 27869827). This variant is reported in the Genome Aggregation Database in seven alleles at a frequency of 0.000054 in the European (non-Finnish) population (version 2.1.1). Based on the available evidence, the c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186CysfsTer15) variant is classified as likely pathogenic for dilated cardiomyopathy.