Submissions for variant NM_001267550.2(TTN):c.81037C>T (p.Arg27013Ter)

dbSNP: rs869038795

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256162	SCV000322337	pathogenic	not provided	2023-01-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 22335739, 25448463)
Eurofins Ntd Llc (ga)	RCV000256162	SCV000335307	likely pathogenic	not provided	2015-09-11	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256713	SCV001433116	pathogenic	Dilated cardiomyopathy 1A	2019-12-18	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265557	SCV001443711	pathogenic	Cardiomyopathy	2020-01-10	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 326 of 363 is predicted to result in loss of normal protein function. This variant has been previously reported as a heterozygous change in patients with dilated cardiomyopathy (PMID: 25448463). ClinVar contains an entry for this variant (Variation ID: 265437). This variant occurs in the A-band of the protein where pathogenic truncating variants associated with dilated cardiomyopathy are enriched (PMID: 22335739). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.81037C>T (p.Arg27013Ter) variant is classified as Pathogenic.
Invitae	RCV001859481	SCV002300028	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg27013*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25448463). This variant is also known as c.53842C>T (p.Arg17948stop). ClinVar contains an entry for this variant (Variation ID: 265437). 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). 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	RCV002347971	SCV002646989	pathogenic	Cardiovascular phenotype	2023-06-13	criteria provided, single submitter	clinical testing	The p.R17948* pathogenic mutation (also known as c.53842C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 53842. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 variant was reported in two related individuals with dilated cardiomyopathy (DCM) from a French Canadian cohort (Chami N et al. Can J Cardiol, 2014 Dec;30:1655-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.