Submissions for variant NM_001267550.2(TTN):c.93166C>T (p.Arg31056Ter)

dbSNP: rs72648250

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209605	SCV000189705	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual 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.
GeneDx	RCV000578520	SCV000680710	pathogenic	not provided	2021-04-23	criteria provided, single submitter	clinical testing	Reported in ClinVar as pathogenic and likely pathogenic (ClinVar Variant ID# 223326; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 25589632, 23975875, 22335739, 24119082, 31317183, 31514951)
Ambry Genetics	RCV000619547	SCV000735415	pathogenic	Cardiovascular phenotype	2022-05-06	criteria provided, single submitter	clinical testing	The p.R21991* pathogenic mutation (also known as c.65971C>T), located in coding exon 166 of the TTN gene, results from a C to T substitution at nucleotide position 65971. This changes the amino acid from an arginine to a stop codon within coding exon 166. This variant 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 truncating alteration has been reported in unrelated individuals with dilated cardiomyopathy (DCM) and has been reported to segregate with disease in families (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Franaszczyk M. PLoS ONE. 2017;12(1):e0169007). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV000705561	SCV000834562	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg31056*) 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 (rs72648250, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 22335739, 28045975). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R29415*. ClinVar contains an entry for this variant (Variation ID: 223326). 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). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000578520	SCV000856943	likely pathogenic	not provided	2017-09-19	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845449	SCV000987534	pathogenic	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002503828	SCV002811990	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-08-12	criteria provided, single submitter	clinical testing