Submissions for variant NM_001267550.2(TTN):c.53355G>A (p.Trp17785Ter)

dbSNP: rs794729273

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184236	SCV000236858	pathogenic	not provided	2018-03-09	criteria provided, single submitter	clinical testing	The W16144X pathogenic variant in the TTN gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This nonsense mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W16144X variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman et al., 2012). W16144X is located in the A-band region of titin, where the majority of truncating and splice site variants associated with cardiomyopathy have been reported (Herman D et al., 2012). We interpret W16144X as a pathogenic variant.
Ambry Genetics	RCV002433824	SCV002745593	likely pathogenic	Cardiovascular phenotype	2019-11-07	criteria provided, single submitter	clinical testing	The p.W8720* variant (also known as c.26160G>A), located in coding exon 105 of the TTN gene, results from a G to A substitution at nucleotide position 26160. This changes the amino acid from a tryptophan to a stop codon within coding exon 105. 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 has been reported in a whole exome sequencing cohort (Yavarna T et al. Hum. Genet., 2015 Sep;134:967-80). 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). As such, this alteration is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398914	SCV004103798	likely pathogenic	TTN-related condition	2023-08-21	criteria provided, single submitter	clinical testing	The TTN c.53355G>A variant is predicted to result in premature protein termination (p.Trp17785*). This variant was reported in an individual with titinopathy (Yavarna et al 2015. PubMed ID: 26077850). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in TTN are expected to be pathogenic. This variant is interpreted as likely pathogenic.