Submissions for variant NM_001267550.2(TTN):c.81321C>G (p.Tyr27107Ter)

dbSNP: rs557312035

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	RCV000209674	SCV000189665	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000209674	SCV000206276	likely pathogenic	Primary dilated cardiomyopathy	2015-06-04	criteria provided, single submitter	clinical testing	The Tyr24539X variant in TTN has been previously reported in 1 Caucasian adult w ith a clinical diagnosis of DCM and segregated with disease in 1 affected relati ve. It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 24539, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM and the majority occur in exons encoding for the A- band region of the protein (Herman 2012, Pugh 2014), where this variant is locat ed. In summary, although additional studies are required to fully establish its clinical significance, the Tyr24539X variant is likely pathogenic.
Invitae	RCV000642760	SCV000764447	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-12-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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). ClinVar contains an entry for this variant (Variation ID: 179759). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 25589632; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr27107*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
AiLife Diagnostics, AiLife Diagnostics	RCV002223189	SCV002501500	pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345521	SCV002653985	pathogenic	Cardiovascular phenotype	2021-12-07	criteria provided, single submitter	clinical testing	The p.Y18042* pathogenic mutation (also known as c.54126C>G), located in coding exon 153 of the TTN gene, results from a C to G substitution at nucleotide position 54126. This changes the amino acid from a tyrosine to a stop codon within coding exon 153. 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 (described as NM_001267550.1:c.81321C>G p.Y27107X) was identified in a cohort of individuals with dilated cardiomyopathy (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV002492596	SCV002796446	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	2021-08-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149958	SCV003838541	likely pathogenic	Cardiomyopathy	2021-06-02	criteria provided, single submitter	clinical testing