Submissions for variant NM_001267550.2(TTN):c.87040C>T (p.Arg29014Ter)

gnomAD frequency: 0.00001  dbSNP: rs776065839

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480710	SCV000568553	pathogenic	not provided	2017-02-09	criteria provided, single submitter	clinical testing	The R27373X pathogenic variant in the TTN gene has been reported in a Dutch family with both peripartum cardiomyopathy and DCM, and was shown to segregate with disease in multiple affected relatives (van Spaendonck-Zwarts et al., 2014). R27373X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other nonsense variants in the TTN gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). And while other truncating TTN variants have been identified in approximately 3% of control alleles, R27373X is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, the R27373X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)
Blueprint Genetics	RCV000480710	SCV000928109	pathogenic	not provided	2018-12-11	criteria provided, single submitter	clinical testing
Invitae	RCV001390945	SCV001592849	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). ClinVar contains an entry for this variant (Variation ID: 420065). This variant is also known as c.82117C>T (p.Arg27373*). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 24558114, 26084686). It has also been observed to segregate with disease in related individuals. 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 sequence change creates a premature translational stop signal (p.Arg29014*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Clinical Genetics Laboratory, Region Ostergotland	RCV001731710	SCV001984987	pathogenic	Dilated cardiomyopathy 1G	2020-12-09	criteria provided, single submitter	clinical testing	PS4, PP1, PP3, PVS1
Ambry Genetics	RCV002356779	SCV002657097	pathogenic	Cardiovascular phenotype	2022-06-08	criteria provided, single submitter	clinical testing	The p.R19949* pathogenic mutation (also known as c.59845C>T), located in coding exon 154 of the TTN gene, results from a C to T substitution at nucleotide position 59845. This changes the amino acid from an arginine to a stop codon within coding exon 154. 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 individuals with dilated cardiomyopathy (DCM), including segregating with disease in one family (van Spaendonck-Zwarts KY et al. Eur Heart J, 2014 Aug;35:2165-73; Akinrinade O et al. Eur Heart J, 2015 Sep;36:2327-37). In addition, 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000480710	SCV001742333	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000480710	SCV001932589	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000480710	SCV001954806	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000480710	SCV001973801	pathogenic	not provided		no assertion criteria provided	clinical testing