Submissions for variant NM_001267550.2(TTN):c.100825C>T (p.Arg33609Ter)

dbSNP: rs1057518195

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412935	SCV000491637	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	Identified in multiple patients with dilated cardiomyopathy in the published literature, however detailed clinical and segregation information were not provided (Carnevale et al., 2020; Verdonschot et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Located in the M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (Carmignac et al., 2007); This variant is associated with the following publications: (PMID: 23975875, 18948003, 27532257, 25589632, 34135346, 32880476, 32969603)
Invitae	RCV000706846	SCV000835920	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg33609*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive TTN-related conditions and/or dilated cardiomyopathy (PMID: 27532257, 32880476, 32969603, 33106378; Invitae). ClinVar contains an entry for this variant (Variation ID: 373074). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002379268	SCV002670676	likely pathogenic	Cardiovascular phenotype	2019-06-14	criteria provided, single submitter	clinical testing	The p.R24544* variant (also known as c.73630C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 73630. This changes the amino acid from an arginine to a stop codon within coding exon 185. This alteration has been reported in a dilated cardiomyopathy (DCM) genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet. Med. 2017 02;19:192-203). This exon is located in the M-band 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 M-band of titin have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants in constitutive exons (PSI >90%) have been found to be significantly associated with DCM, though truncating variants in the A-band are the most common cause of 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration in association with cardiomyopathy remains unclear.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000412935	SCV001799533	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000412935	SCV001929283	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412935	SCV001952660	likely pathogenic	not provided		no assertion criteria provided	clinical testing