Submissions for variant NM_001267550.2(TTN):c.35794G>T (p.Glu11932Ter)

gnomAD frequency: 0.00001  dbSNP: rs878854299

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231913	SCV000286600	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu11932*) 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 clinical features of autosomal recessive centronuclear myopathy (PMID: 29691892). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 238750). 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). 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). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000657941	SCV000338622	uncertain significance	not provided	2018-02-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000657941	SCV000779710	pathogenic	not provided	2021-11-15	criteria provided, single submitter	clinical testing	Observed with a splice variant on the opposite allele (in trans) in a patient with a congenital TTN-related disorder in published literature (Oates et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32778822, 29691892)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663407	SCV000786695	uncertain significance	Early-onset myopathy with fatal cardiomyopathy		criteria provided, single submitter	research	The heterozygous p.Glu11932X variant in TTN has been identified in the compound heterozygous state by our project in one individual with early onset myopathy. The p.Glu11932X variant has not been reported in the literature however, it has been reported as a VUS for dilated cardiomyopathy in ClinVar. The lab reportedly identified this variant in 2 individuals, though no additional evidence was provided. Compound heterozygous loss of function TTN variants have been reported in individuals with early onset myopathy and cardiomyopathy. This variant has been identified in <0.01% (2/92728) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs768073446). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In summary, while the predicted impact of this variant provides some suspicion for a pathogenic role, the clinical significance of the p.Glu11932X variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000657941	SCV001152960	likely pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288919	SCV002580696	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-02-01	criteria provided, single submitter	clinical testing