Submissions for variant NM_001267550.2(TTN):c.69421_69422insAAAAG (p.Gly23141fs)

dbSNP: rs1247353236

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378156	SCV001575662	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly23141Glufs*38) 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 present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with TTN-related conditions (PMID: 30535219, 31931689). ClinVar contains an entry for this variant (Variation ID: 1067013). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV004995726	SCV005528170	likely pathogenic	Cardiovascular phenotype	2024-07-30	criteria provided, single submitter	clinical testing	The c.42226_42227insAAAAG variant, located in coding exon 152 of the TTN gene, results from an insertion of 5 nucleotides at position 42226, causing a translational frameshift with a predicted alternate stop codon (p.G14076Efs*38). 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005051900	SCV005685163	likely pathogenic	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2024-07-10	criteria provided, single submitter	clinical testing	The TTN c.69421_69422insAAAAG (p.Gly23141Glufs*38) variant has been reported in 2 individuals affected with dilated cardiomyopathy or atrial fibrillation (Choi SH et al., PMID: 30535219; Ramchand J et al., PMID: 31931689). This variant is only observed on 1 out of 31,354 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542649	SCV001760065	likely pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure		no assertion criteria provided	clinical testing