Submissions for variant NM_001267550.2(TTN):c.6820C>T (p.Gln2274Ter)

dbSNP: rs145649088

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598721	SCV000710697	likely pathogenic	not provided	2018-02-22	criteria provided, single submitter	clinical testing	A likely pathogenic variant has been identified in the TTN gene. The Q2274X variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The Q2274X variant 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. Truncating TTN variants have been reported in approximately 3% of control alleles, and the majority of truncating pathogenic variants associated with DCM have been reported in the A-band (Herman et al., 2012). However, the Q2274X variant is located in one of the constitutive exons in the proximal I-band region and recent studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are also significantly associated with DCM (Schafer et al., 2017; Deo et al., 2017).
Invitae	RCV001369643	SCV001566087	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-07-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2274*) 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: 504376). 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.
Revvity Omics, Revvity	RCV000598721	SCV003822905	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003302927	SCV004004267	likely pathogenic	Cardiovascular phenotype	2023-03-31	criteria provided, single submitter	clinical testing	The p.Q2228* variant (also known as c.6682C>T), located in coding exon 28 of the TTN gene, results from a C to T substitution at nucleotide position 6682. This changes the amino acid from a glutamine to a stop codon within coding exon 28. 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 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003945452	SCV004761867	likely pathogenic	TTN-related condition	2023-11-21	criteria provided, single submitter	clinical testing	The TTN c.6820C>T variant is predicted to result in premature protein termination (p.Gln2274*). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Other nearby loss-of-function variants have been reported in cases of autosomal recessive TTN-related myopathies (c.6322G>T, Mazzarotto et al 2020. PubMed ID: 31983221; c.8353G>T, Akinrinade et al 2015. PubMed ID: 26084686). This variant is located in the TTN protein I-band region. RNA sequencing studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (Exon 32, PSI of 100%, Roberts et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts et al. 2015. PMID: 25589632; Herman et al. 2012. PMID: 22335739). However, many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy et al. 2013. PMID: 23975875; Chauveau et al. 2014. PubMed ID: 24105469; Evilä et al. 2016. PubMed ID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is interpreted as likely pathogenic for both autosomal recessive and dominant TTN-related disorders.