Submissions for variant NM_001267550.2(TTN):c.56572C>T (p.Arg18858Ter)

gnomAD frequency: 0.00002  dbSNP: rs745376275

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001210866	SCV001382375	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg18858*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 22335739, 27532257, 30109841). This variant is also known as p.R9793X. ClinVar contains an entry for this variant (Variation ID: 941144). 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). 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	RCV001780121	SCV002021462	likely pathogenic	not provided	2020-10-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436811	SCV002747803	likely pathogenic	Cardiovascular phenotype	2020-12-01	criteria provided, single submitter	clinical testing	The p.R9793* variant (also known as c.29377C>T), located in coding exon 117 of the TTN gene, results from a C to T substitution at nucleotide position 29377. This changes the amino acid from an arginine to a stop codon within coding exon 117. 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 was reported in an individual with dilated cardiomyopathy (DCM) who also had an MYBPC3 truncation variant; however, clinical details were limited (Fan LL et al. Cardiol Young, 2018 Dec;28:1410-1414). This variant (also referred to as c.56572C>T p.R18858X) has been detected in additional individuals reported to have DCM or who underwent DCM genetic testing (Herman DS et al. N Engl J Med. 2012 Feb;366(7):619-28; Walsh R et al. Genet Med. 2017 02;19(2):192-203). In addition to the clinical data presented in the literature, 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	RCV002484145	SCV002783040	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	2021-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155372	SCV003845068	likely pathogenic	Primary familial dilated cardiomyopathy	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.48868C>T (p.Arg16290X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.1e-05 in 185344 control chromosomes. c.48868C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001780121	SCV003923864	pathogenic	not provided	2022-10-07	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 A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 27532257, 34758253, 30109841)
Genomics England Pilot Project, Genomics England	RCV001542650	SCV001760066	likely pathogenic	Dilated cardiomyopathy 1G		no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV001542650	SCV004022123	likely pathogenic	Dilated cardiomyopathy 1G	2023-07-21	no assertion criteria provided	research	The variant NM_001267550.2:c.56572C>T (chr2:178599221) in TTN was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.