Submissions for variant NM_001267550.2(TTN):c.9610C>T (p.Arg3204Ter)

gnomAD frequency: 0.00003  dbSNP: rs757836789

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726264	SCV000343263	uncertain significance	not provided	2016-07-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000726264	SCV000618718	likely pathogenic	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); Identified in patients with DCM referred for genetic testing at GeneDx and in published literature (Bourfiss et al., 2022); Reported in at least one individual with early onset atrial fibrillation who also has a pathogenic variant in the MYH7 gene (Choi et al., 2018; Yoneda et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27625338, 27869827, 22335739, 26701604, 23975875, 25589632, 33226272, 30535219, 36264615, 34495297)
Illumina Laboratory Services, Illumina	RCV000779289	SCV000915871	uncertain significance	TTN-Related Disorders	2018-11-05	criteria provided, single submitter	clinical testing	The TTN c.9610C>T (p.Arg3204Ter) variant is a stop-gained variant that is predicted to result in an absent or truncated protein. A literature search was conducted for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database, but this frequency is based on one allele only in a region of good sequencing coverage. The variant is therefore presumed to be rare. Based on the potential impact of stop-gained variants and the lack of clarifying evidence, the p.Arg3204Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000822916	SCV000963741	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3204*) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy and/or early-onset atrial fibrillation (PMID: 30535219; Invitae). ClinVar contains an entry for this variant (Variation ID: 288998). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae 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, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002446529	SCV002683233	likely pathogenic	Cardiovascular phenotype	2023-03-09	criteria provided, single submitter	clinical testing	The p.R3158* variant (also known as c.9472C>T), located in coding exon 39 of the TTN gene, results from a C to T substitution at nucleotide position 9472. This changes the amino acid from an arginine to a stop codon within coding exon 39. This exon is located in the I-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 alteration has been reported in a case control study looking at the correlation between TTN truncating alterations and atrial fibrillation (Choi SH et al. JAMA, 2018 12;320:2354-2364). 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). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic.
GenomeConnect, ClinGen	RCV001787095	SCV002029130	not provided	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		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 09-14-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.