Submissions for variant NM_001267550.2(TTN):c.3034C>T (p.Arg1012Ter)

dbSNP: rs397517547

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040169	SCV000063860	likely pathogenic	Primary dilated cardiomyopathy	2015-05-07	criteria provided, single submitter	clinical testing	The p.Arg1012X variant in TTN has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 1012, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A -band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expr essed in the heart (Roberts 2015). The p.Arg1012X variant is located in the high ly expressed exon 18 in the near Z-disk band. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg1012X variant is likely pathogenic.
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000754723	SCV000882610	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-10-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314678	SCV001505220	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1012*) 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 present in population databases (rs397517547, gnomAD 0.0009%). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with autosomal dominant dilated cardiomyopathy (PMID: 24503780, 27532257, 29029073; internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 46899). This variant is located in the Z band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 33449170, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002433512	SCV002750860	uncertain significance	Cardiovascular phenotype	2023-01-09	criteria provided, single submitter	clinical testing	The p.R966* variant (also known as c.2896C>T), located in coding exon 16 of the TTN gene, results from a C to T substitution at nucleotide position 2896. This changes the amino acid from an arginine to a stop codon within coding exon 16. 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 alteration (referred to as p.Arg1012X, c.3034C>T) was reported in one individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.