Submissions for variant NM_001267550.2(TTN):c.61555C>T (p.Arg20519Ter)

dbSNP: rs794729278

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001052127	SCV001216321	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg20519*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. 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 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: 202397). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798646	SCV002042580	likely pathogenic	Cardiomyopathy	2019-06-14	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223811	SCV002502747	likely pathogenic	not provided	2021-09-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453672	SCV002616899	likely pathogenic	Cardiovascular phenotype	2022-10-03	criteria provided, single submitter	clinical testing	The p.R11454* variant (also known as c.34360C>T), located in coding exon 131 of the TTN gene, results from a C to T substitution at nucleotide position 34360. This changes the amino acid from an arginine to a stop codon within coding exon 131. 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503723	SCV002816503	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	2021-10-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002223811	SCV003813615	likely pathogenic	not provided	2022-07-11	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV003227468	SCV003924040	pathogenic	Dilated cardiomyopathy 1G		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.34360C>T in Exon 132 of the TTN gene that results in the amino acid substitution p.Arg11454* was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic with 2 stars, criteria provided, multiple submitters, no conflicts (202397). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.