Submissions for variant NM_001267550.2(TTN):c.59205del (p.Glu19735fs)

dbSNP: rs397517643

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040417	SCV000064108	likely pathogenic	Primary dilated cardiomyopathy	2012-05-24	criteria provided, single submitter	clinical testing	The Glu17167fs variant in TTN has not been reported in the literature nor previo usly identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 17167 and lead to a pre mature termination codon 24 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Heterozygous loss of function of the TTN gene is strongly associated with DCM (Herman 2012). In summary, this va riant is likely to be pathogenic, though additional daa is needed to establish t his with certainty.
GeneDx	RCV000184316	SCV000236941	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	Reported in an individual with left ventricular noncompaction (Mazzarotto et al., 2021); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar (ClinVar Variant ID 47147; ClinVar); This variant is associated with the following publications: (PMID: 22335739, 23975875, 33500567)
Invitae	RCV000458722	SCV000542299	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu19735Aspfs*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 left ventricular noncompaction (PMID: 33500567). This variant is also known as c.51501delG (p.Glu17167fs). ClinVar contains an entry for this variant (Variation ID: 47147). 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). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004944	SCV001164468	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Glu19735AspfsTer24 variant in TTN was identified by our study in the compound heterozygous state, with a VUS, in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 19735, 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 LGMD. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu19735AspfsTer24 variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015).
Ambry Genetics	RCV002321524	SCV002610240	likely pathogenic	Cardiovascular phenotype	2021-05-10	criteria provided, single submitter	clinical testing	The c.32010delG variant, located in coding exon 127 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 32010, causing a translational frameshift with a predicted alternate stop codon (p.E10670Dfs*24). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med. 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med. 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet. 2017 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.