Submissions for variant NM_001267550.2(TTN):c.658C>T (p.Arg220Ter)

dbSNP: rs748313513

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184292	SCV000236917	likely pathogenic	not provided	2014-07-09	criteria provided, single submitter	clinical testing	p.Arg220Stop (CGA>TGA): c.658 C>T in exon 5 of the TTN gene (NM_001256850.1). The R220X variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R220X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R220X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman D et al., 2012). Furthermore, R220X is not located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001339180	SCV001532901	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg220*) 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 (rs748313513, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 202433). This variant is located in the Z band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 33449170, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). 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	RCV002372130	SCV002667607	likely pathogenic	Cardiovascular phenotype	2025-02-21	criteria provided, single submitter	clinical testing	The p.R220* variant (also known as c.658C>T), located in coding exon 4 of the TTN gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from an arginine to a stop codon within coding exon 4. This exon is located in the Z-disk 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 individual(s) with features consistent with dilated cardiomyopathy (DCM) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant 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 (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; Akhtar MM et al. Circ Heart Fail, 2020 Oct;13:e006832; Massier M et al. Clin Genet, 2025 Jan). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486746	SCV004240091	likely pathogenic	Cardiomyopathy	2022-10-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000184292	SCV005198938	likely pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing