Submissions for variant NM_001267550.2(TTN):c.16288C>T (p.Arg5430Ter)

gnomAD frequency: 0.00001  dbSNP: rs772235481

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000312986	SCV000334048	uncertain significance	not provided	2015-09-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814903	SCV000955340	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.Arg5430*) 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 individual(s) with congenital myopathy (PMID: 33449170). This variant has been reported in individual(s) with atrial fibrillation (PMID: 30535219); however, the role of the variant in this condition is currently unclear. This variant is also known as c.16513C>T. ClinVar contains an entry for this variant (Variation ID: 282527). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, 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.
Athena Diagnostics	RCV000312986	SCV001880220	likely pathogenic	not provided	2020-08-31	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant occurs in the I-band of the TTN gene, and is a nonsense variant in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). Nonsense and other truncating variants in TTN have been reported in patients with dominant cardiomyopathy, dominant tibial muscular dystrophy, recessive salih myopathy, recessive limb-girdle muscular dystrophy, and recessive centronuclear myopathy (OMIM# 188840). However, these types of variants have also been found in healthy individuals (PMID: 25589632). An alternative, in-frame, transcription start site has been identified between exons 239 and 240 (NM_001267550.1), suggesting that variants occurring in exons 1-239 may be rescued via transcription from the alternative site (PMID: 26473617). This variant falls within this region (exon 55). Cardiomyopathy and muscular dystrophy patients are reported to have truncating variants in the A-band and M-band of TTN, respectively, statistically more often than individuals in the general population (PMID: 25589632).
GeneDx	RCV000312986	SCV002759026	uncertain significance	not provided	2022-05-31	criteria provided, single submitter	clinical testing	Reported in a patient referred for whole exome sequencing and in an unrelated patient with early onset atrial fibrillation (Posey et al., 2017; Choi et al., 2018); however, detailed clinical information was not provided; Not observed at significant frequency in large population cohorts (gnomAD); 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); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 27625338, 27869827, 30535219, 27959697)
Revvity Omics, Revvity	RCV000312986	SCV003822139	uncertain significance	not provided	2020-02-20	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003992259	SCV004810222	uncertain significance	Dilated cardiomyopathy 1G	2024-04-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000415222	SCV000328733	pathogenic	Dilated cardiomyopathy 1G; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Hypertrophic cardiomyopathy 9	2015-07-04	no assertion criteria provided	clinical testing	Our laboratory reported two molecular diagnoses in NOTCH1 (NM_017617.3, c.6348C>G) and TTN (NM_133378.3, c.12556C>T)in one individual with reported features of delayed speech, dysmorphic features (hypertelorism with widened nasal bridge, over folded helices and prominent long philtrum), congenital heart disease (tricuspid valve dysplasia, sinus of valsalva dilatation and atrial enlargement), pulmonary lymphangiectasia, and transient neonatal cholestasis. The variant in NOTCH1 is predicted to cause a nonsense mutation and is categorized as deleterious by ACMGG guidelines [PMID: 18414213].
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319194	SCV004023218	likely pathogenic	Tip-toe gait	2022-10-10	flagged submission	clinical testing	Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.