Submissions for variant NM_001267550.2(TTN):c.77147_77150del (p.Val25715_Ser25716insTer)

dbSNP: rs1466647934

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545046	SCV000642464	likely pathogenic	Dilated cardiomyopathy 1G	2017-05-22	criteria provided, single submitter	clinical testing	This sequence change deletes 4 nucleotides from exon 326 of the TTN mRNA (c.77147_77150delCTCT), causing a frameshift at codon 25716. This creates a premature translational stop signal (p.Ser25716*) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378784	SCV001576437	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2020-10-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Likely Pathogenic. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). This sequence change deletes 4 nucleotides from exon 326 of the TTN mRNA (c.77147_77150delCTCT), causing a frameshift at codon 25716. This creates a premature translational stop signal (p.Ser25716*) and is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV004024028	SCV005020647	likely pathogenic	Cardiovascular phenotype	2023-10-13	criteria provided, single submitter	clinical testing	The c.49952_49955delCTCT variant, located in coding exon 153 of the TTN gene, results from a deletion of 4 nucleotides at nucleotide positions 49952 to 49955, causing a translational frameshift with a predicted alternate stop codon (p.S16651*). 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 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 majority of available evidence to date, this variant is likely to be pathogenic.