Submissions for variant NM_001267550.2(TTN):c.58195C>T (p.Arg19399Ter)

gnomAD frequency: 0.00001  dbSNP: rs768073446

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497418	SCV000589889	likely pathogenic	not provided	2022-07-18	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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; 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); This variant is associated with the following publications: (PMID: 23975875)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663408	SCV000786696	uncertain significance	Early-onset myopathy with fatal cardiomyopathy		criteria provided, single submitter	research	The heterozygous p.Arg19399X variant in TTN has been identified in the compound heterozygous state by our project in one individual with early onset myopathy. The p.Arg19399X variant has not been reported in the literature however it has been identified in 0.01% (2/70872) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765879488). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Compound heterozygous loss of function TTN variants have been reported in individuals with early onset myopathy and cardiomyopathy. In summary, while the predicted impact of this variant provides some suspicion for a pathogenic role, the clinical significance of the p.Arg19399X variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049350	SCV001213396	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-12-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 432196). This variant has not been reported in the literature in individuals affected with TTN-related conditions. 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 sequence change creates a premature translational stop signal (p.Arg19399*) 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 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798861	SCV002042559	uncertain significance	Cardiomyopathy	2020-01-24	criteria provided, single submitter	clinical testing