Submissions for variant NM_001267550.2(TTN):c.104399del (p.Arg34800fs)

gnomAD frequency: 0.00001  dbSNP: rs747662439

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000287782	SCV000342134	likely pathogenic	not provided	2016-06-21	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000287782	SCV001450350	pathogenic	not provided	2017-10-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000287782	SCV001714015	uncertain significance	not provided	2020-02-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000287782	SCV002021514	likely pathogenic	not provided	2020-10-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859673	SCV002265878	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg34800Lysfs*10) 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 (rs747662439, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 288119). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225939	SCV003922159	likely pathogenic	TTN-related myopathy	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Arg34800LysfsTer10 variant in TTN was identified by our study in two siblings with limb girdle muscular dystrophy. Familial exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 1678017). The p.Arg34800LysfsTer10 variant in TTN has not been previously reported in individuals with autosomal recessive limb girdle muscular dystrophy 10 but has been identified in 0.004% (1/24756) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs747662439). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 288119) and has conflicting interpretations of pathogenicity. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 34800 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive limb girdle muscular dystrophy 10. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive limb girdle muscular dystrophy 10. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).
Ambry Genetics	RCV003298344	SCV004004251	likely pathogenic	Cardiovascular phenotype	2023-03-24	criteria provided, single submitter	clinical testing	The c.77204delG variant, located in coding exon 185 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 77204, causing a translational frameshift with a predicted alternate stop codon (p.R25735Kfs*10). This exon is located in the M-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 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 M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017588	SCV004847623	likely pathogenic	Primary dilated cardiomyopathy	2019-01-25	criteria provided, single submitter	clinical testing	The p.Arg32232LysfsX10 variant in TTN has not been reported in individuals with TTN-associated diseases, such as dilated cardiomyopathy and neuromuscular conditions but has been identified in 3/278880 chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has been reported by a clinical laboratory in ClinVar (variation ID #504393). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 32232 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. TTN truncating variants located in exons that are highly expressed in the heart are strongly associated with autosomal dominant DCM, particularly if they are located in the A-band (Herman 2012, Pugh 2014, Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Arg32232LysfsX10 variant is located in a highly expressed exon in the M-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000287782	SCV005198891	likely pathogenic	not provided	2022-06-08	criteria provided, single submitter	clinical testing