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

gnomAD frequency: 0.00001  dbSNP: rs878854299

Total submissions: 7

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	2024-11-04	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. This variant has been reported in individual(s) with autosomal dominant non-ischemic cardiomyopathy (internal data); however, the role of the variant in this condition is currently unclear. 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, 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). 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	pathogenic	Early-onset myopathy with fatal cardiomyopathy	2025-01-09	criteria provided, single submitter	research	The heterozygous p.Glu11932Ter variant in TTN was identified by our study in one individual with early onset myopathy, in the compound heterozygous state along with another pathogenic variant. The phase of these variants is unknown at this time. The p.Glu11932Ter variant has been reported in 6 families with TTN-related myopathy (PMID: 29691892), and has been identified in 0.003% (30/1171268) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs878854299). 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. Of the 7 affected individuals, 4 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Glu11932Ter variant is pathogenic (Variation ID: 1067510, 2938083, 404786, 223329; PMID: 29691892). This variant has also been reported in ClinVar (Variation ID: 238750) and has been interpreted as pathogenic/likely pathogenic by Labcorp, GeneDx, MGZ Medical Genetics Center, and CeGaT Center for Human Genetics Tuebingen, and as a variant of uncertain significance by Eurofins Ntd Llc. This nonsense variant leads to a premature termination codon at position 11932 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 TTN-related myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive TTN-related myopathy. ACMG/AMP Criteria applied: PM3_very-strong, PVS1, PM2_supporting (Richards 2015).
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
Fulgent Genetics, Fulgent Genetics	RCV005025386	SCV005655273	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	2024-05-28	criteria provided, single submitter	clinical testing