Submissions for variant NM_001267550.2(TTN):c.70000del (p.Glu23334fs)

dbSNP: rs1131691811

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493910	SCV000582903	pathogenic	not provided	2021-05-19	criteria provided, single submitter	clinical testing	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; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002329175	SCV002627854	likely pathogenic	Cardiovascular phenotype	2020-11-03	criteria provided, single submitter	clinical testing	The c.42805delG variant, located in coding exon 153 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 42805, causing a translational frameshift with a predicted alternate stop codon (p.E14269Kfs*3). 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, 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). As such, this alteration is classified as likely pathogenic.