Submissions for variant NM_001267550.2(TTN):c.4714C>T (p.Arg1572Ter)

dbSNP: rs1554008881

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599182	SCV000709862	uncertain significance	not specified	2015-07-02	criteria provided, single submitter	clinical testing	The R1572X variant in the TTN gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. R1572X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Additionally, the R1572X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). Furthermore, R1572X is not located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Klaassen Lab, Charite University Medicine Berlin	RCV002062110	SCV002495735	likely pathogenic	Left ventricular noncompaction cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002341535	SCV002636225	uncertain significance	Cardiovascular phenotype	2022-05-23	criteria provided, single submitter	clinical testing	The p.R1526* variant (also known as c.4576C>T), located in coding exon 25 of the TTN gene, results from a C to T substitution at nucleotide position 4576. This changes the amino acid from an arginine to a stop codon within coding exon 25. This exon is located in the near Z-disk 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 NM_001267550.1:c.4714C>T p.R1572*) has been detected in a left ventricular noncompaction cardiomyopathy cohort (Schultze-Berndt A et al. Front Pediatr, 2021 Sep;9:722926). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Based on available evidence to date, the clinical significance of this alteration remains unclear.