Submissions for variant NM_001267550.2(TTN):c.103771C>T (p.Arg34591Ter)

gnomAD frequency: 0.00001  dbSNP: rs967542291

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203246	SCV001374402	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-07-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg34591*) 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 0.006%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 36264615). ClinVar contains an entry for this variant (Variation ID: 934781). 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, Invitae 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.
Revvity Omics, Revvity	RCV001780110	SCV002021466	likely pathogenic	not provided	2021-03-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004033565	SCV003887513	likely pathogenic	Cardiovascular phenotype	2023-01-26	criteria provided, single submitter	clinical testing	The c.76576C>T (p.R25526*) alteration, located in exon 186 (coding exon 185) of the TTN gene, consists of a C to T substitution at nucleotide position 76576. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 25526. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. _x000D_ _x000D_ Based on the available evidence, the c.76576C>T (p.R25526*) alteration is classified as likely pathogenic for autosomal recessive Salih myopathy and/or TTN-related limb-girdle muscular dystrophy; however, the clinical significance of this alteration for autosomal dominant cardiomyopathy remains unclear. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/248846) total alleles studied. The highest observed frequency was 0.011% (2/17954) of East Asian alleles. 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%). Truncating variants in the M-band have been reported in association with autosomal recessive skeletal myopathy phenotypes, Salih myopathy and TTN-related limb-girdle muscular dystrophy (Ceyhan-Birsoy, 2013; De Cid, 2015). Based on the available evidence, this alteration is classified as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001780110	SCV005198892	likely pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001780110	SCV005373285	likely pathogenic	not provided	2024-03-25	criteria provided, single submitter	clinical testing	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 M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (PMID: 17444505); Identified by exome sequencing in an individual with DCM; however, detailed clinical information was not provided (PMID: 36264615); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17444505, 35177841, 33226272, 36264615)
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004764957	SCV005375103	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing