Submissions for variant NM_001267550.2(TTN):c.96901del (p.Arg32301fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003042684	SCV003331345	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg32301Glufs*24) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive TTN-related conditions (Invitae). 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: 2114231). 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). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003042683	SCV003761419	uncertain significance	TTN-related myopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous variant p.Arg32301GlufsTer24 variant in TTN was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 202529), in one individual with limb-girdle muscular dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 202529), however the phase of these variants are unknown at this time. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 32301 and leads to a premature termination codon 24 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy 10. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for limb-girdle muscular dystrophy 10. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).