Submissions for variant NM_001267550.2(TTN):c.9448C>T (p.Arg3150Ter)

gnomAD frequency: 0.00001  dbSNP: rs146572907

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000338901	SCV000334544	uncertain significance	not provided	2015-08-20	criteria provided, single submitter	clinical testing
Invitae	RCV000535764	SCV000643924	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3150*) 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 (rs146572907, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 32998006; Invitae). ClinVar contains an entry for this variant (Variation ID: 282852). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae 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, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
Genetics and Genomics Program, Sidra Medicine	RCV001293221	SCV001434220	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Suma Genomics	RCV001815380	SCV002062080	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J; Early-onset myopathy with fatal cardiomyopathy		criteria provided, single submitter	clinical testing
GeneDx	RCV000338901	SCV002512844	likely pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Identified in patients with DCM in the published literature (Corden et al., 2019; Anderson et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32998006, 31251381)
Ambry Genetics	RCV002374458	SCV002684584	likely pathogenic	Cardiovascular phenotype	2022-10-14	criteria provided, single submitter	clinical testing	The p.R3104* variant (also known as c.9310C>T), located in coding exon 38 of the TTN gene, results from a C to T substitution at nucleotide position 9310. This changes the amino acid from an arginine to a stop codon within coding exon 38. This exon is located in the I-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 (also referred to as p.R3150*, c.9448C>T, and rs146572907) has been detected in a dilated cardiomyopathy (DCM) cohort and in exome cohorts not selected for the presence of cardiomyopathy; however, clinical details were limited (Georgi B et al. PLoS Genet, 2013 May;9:e1003484; Roberts AM et al. Sci Transl Med. 2015 Jan;7(270):270ra6; Anderson JL et al. Am J Cardiol, 2020 12;137:97-102; Park J et al. Nat Med, 2021 01;27:66-72). 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 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 majority of available evidence to date, this variant is likely to be pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000338901	SCV001739609	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000338901	SCV001931557	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000338901	SCV001970988	likely pathogenic	not provided		no assertion criteria provided	clinical testing