Submissions for variant NM_001267550.2(TTN):c.106049del (p.Thr35350fs)

dbSNP: rs1250336644

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599195	SCV000710057	likely pathogenic	not provided	2017-07-06	criteria provided, single submitter	clinical testing	The c.101126delC variant in the TTN gene has not been reported to our knowledge. It is not observed in large populationcohorts (Lek et al., 2016). This variant causes a shift in reading frame starting at codon threonine 33709, changing it to amethionine, and creating a premature stop codon at position 55 of the new reading frame, denoted p.Thr33709MetfsX55. Thisvariant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele throughnonsense-mediated mRNA decay. Other frameshift variants in the TTN gene have been reported in the Human Gene MutationDatabase in association with cardiomyopathy (Stenson et al., 2014). However, c.101126delC is not located in the A-bandregion of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al.,2012). Other truncating variants in the M-band of titin, where this variant occurs, have been reported in association with anautosomal recessive early-onset myopathy with cardiomyopathy (Carmignac et al., 2007), and heterozygous parents werereportedly healthy. Furthermore, other nonsense and frameshift TTN variants have been reported in approximately 3% ofcontrol alleles (Herman et al., 2012).
Invitae	RCV001379954	SCV001577867	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr35350Metfs*55) 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 TTN-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 503763). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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). 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.
Revvity Omics, Revvity	RCV000599195	SCV002021465	likely pathogenic	not provided	2022-01-29	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289893	SCV002580460	likely pathogenic	Early-onset myopathy with fatal cardiomyopathy	2021-09-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476344	SCV002783092	likely 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	2021-07-05	criteria provided, single submitter	clinical testing