Submissions for variant NM_001267550.2(TTN):c.93897del (p.Phe31299fs)

dbSNP: rs397517758

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040804	SCV000064495	likely pathogenic	Primary dilated cardiomyopathy	2014-08-25	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000184359	SCV000236984	pathogenic	not provided	2014-05-08	criteria provided, single submitter	clinical testing	c.88974delT: p.Phe29658LeufsX14 (F29658LfsX14) in exon 289 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces is: CATT{T}AGCG. Truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic dilated cardiomyopathy (DCM) (Herman D et al., 2012). However, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman D et al., 2012). TTN mutations may also be associated with congenital cardiac and skeletal myopathies, hereditary myopathy with early respiratory failure, tibial muscular dystrophy, and limb-girdle muscular dystrophy (Lange S et al., 2005; Hackman P et al., 2002; Carmignac V et al., 2007; Hackman P et al., 2008). Although the c.88974delT mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Phenylalanine 29658, changing it to a Leucine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Phe29658LeufsX14. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.88974delT is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman et al., 2012). In summary, c.88974delT in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852834	SCV002306922	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-01-22	criteria provided, single submitter	clinical testing	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. 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). ClinVar contains an entry for this variant (Variation ID: 47535). This variant is also known as c.86193del (p.Phe28731LeufsX14). This premature translational stop signal has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 24503780). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe31299Leufs*14) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics	RCV002362649	SCV002663308	pathogenic	Cardiovascular phenotype	2022-05-03	criteria provided, single submitter	clinical testing	The c.66702delT pathogenic mutation, located in coding exon 166 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 66702, causing a translational frameshift with a predicted alternate stop codon (p.F22234Lfs*14). 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%). This variant (referred to as c.93897del, p.Phe31299LeufsX14) has been detected in a dilated cardiomyopathy cohort (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Walsh R et al. Genet Med, 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 01;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.