Submissions for variant NM_001267550.2(TTN):c.98551C>T (p.Arg32851Ter)

dbSNP: rs553821887

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209760	SCV000189737	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in two individuals in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Invitae	RCV001201784	SCV001372875	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-09-05	criteria provided, single submitter	clinical testing	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. This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 223261). 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). This variant is present in population databases (rs553821887, ExAC 0.006%). This sequence change results in a premature translational stop signal in the TTN gene (p.Arg32851*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics	RCV002363044	SCV002665480	likely pathogenic	Cardiovascular phenotype	2020-11-25	criteria provided, single submitter	clinical testing	The p.R23786* variant (also known as c.71356C>T), located in coding exon 179 of the TTN gene, results from a C to T substitution at nucleotide position 71356. This changes the amino acid from an arginine to a stop codon within coding exon 179. 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 (referred to as p.R32851*, c.98551C>T) has been detected in a community-based cohort; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). 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). As such, this alteration is classified as likely pathogenic.
GeneDx	RCV002460993	SCV002756681	pathogenic	not provided	2022-11-20	criteria provided, single submitter	clinical testing	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); Has not been previously published as pathogenic or benign in association with a titinopathy phenotype to our knowledge; 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: 25589632, 27625338, 22335739, 35177841)