Submissions for variant NM_001267550.2(TTN):c.35828dup (p.Glu11945Argfs)

gnomAD frequency: 0.00001  dbSNP: rs765879488

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663411	SCV000786699	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J		criteria provided, single submitter	research	The heterozygous p.Glu11945fs variant in TTN has been identified in the compound heterozygous state by our project in one individual with Limb Girdle Muscular Dystrophy. This variant has not been reported in the literature but compound heterozygous loss of function variants have been previously described in individuals with Limb Girdle Muscular Dystrophy (source: ClinVar). This varint has been identified in <0.01% (2/70872) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765879488). AAlthough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704886	SCV000833858	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-06-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu11945Argfs*6) 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 (rs765879488, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with limb girdle weakness and/or skeletal muscle disorders (PMID: 29435569, 32528171; Invitae). This variant has been reported in individual(s) with dilated cardiomyopathy (Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 548989). 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, Invitae 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, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586855	SCV005038525	likely pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PVS1+PM2