Submissions for variant NM_001267550.2(TTN):c.92404G>T (p.Gly30802Ter)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002364238	SCV002659235	likely pathogenic	Cardiovascular phenotype	2020-06-30	criteria provided, single submitter	clinical testing	The p.G21737* variant (also known as c.65209G>T), located in coding exon 166 of the TTN gene, results from a G to T substitution at nucleotide position 65209. This changes the amino acid from a glycine to a stop codon within coding exon 166. 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 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.