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	2024-12-13	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); Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); This variant is associated with the following publications: (PMID: 23975875, 36264615)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663408	SCV000786696	likely pathogenic	Early-onset myopathy with fatal cardiomyopathy		criteria provided, single submitter	research	The heterozygous p.Arg19399Ter variant in TTN was identified by our study in one individual with early onset myopathy, in the compound heterozygous state along with a likely pathogenic variant. The phase of these variants are unknown at this time. The p.Arg19399Ter variant has not been previously reported in the literature in individuals with TTN-related myopathy, but has been identified in 0.002% (1/44668) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs768073446). 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: 432196) and has been interpreted as likely pathogenic by Labcorp (formerly Invitae) and GeneDx, and a variant of uncertain significance by CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario. This nonsense variant leads to a premature termination codon at position 19339 which is predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive early onset myopathy. Multiple variants in the same region as p.Arg19399Ter have been reported in association with disease in TTN-related myopathy, suggesting that this variant is in a hot spot and slightly supports pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive early onset myopathy. ACMG/AMP Criteria applied: PVS1, PM1_supporting, PM2_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049350	SCV001213396	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-10-07	criteria provided, single submitter	clinical testing	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. 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 432196). 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