Submissions for variant NM_001267550.2(TTN):c.82657G>T (p.Gly27553Ter)

dbSNP: rs869178171

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000579232	SCV000680712	pathogenic	not provided	2018-06-04	criteria provided, single submitter	clinical testing	The G25912X pathogenic variant in the TTN gene, described as G18488X due to the use of an alternative transcript, has been previously reported in association with DCM (Chami et al., 2014). G25912X is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Although other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012), G25912X is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, G25912X is not observed in large population cohorts (Lek et al., 2016).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622457	SCV000740469	pathogenic	Primary familial dilated cardiomyopathy	2016-06-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763467	SCV000894244	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001379494	SCV001577306	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-11-24	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: 488810). This variant is also known as NM_003319.4:c.55462G>T (p.Gly18488Stop). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25448463). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly27553*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798900	SCV002043008	pathogenic	Cardiomyopathy	2023-06-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159974	SCV003858743	likely pathogenic	Cardiovascular phenotype	2023-03-10	criteria provided, single submitter	clinical testing	The p.G18488* variant (also known as c.55462G>T), located in coding exon 153 of the TTN gene, results from a G to T substitution at nucleotide position 55462. This changes the amino acid from a glycine to a stop codon within coding exon 153. 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 has been detected in a dilated cardiomyopathy cohort (Chami N et al. Can J Cardiol, 2014 Dec;30:1655-61). 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.