Submissions for variant NM_001267550.2(TTN):c.56495G>A (p.Trp18832Ter)

dbSNP: rs1576247054

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008693	SCV001168472	likely pathogenic	not provided	2019-03-04	criteria provided, single submitter	clinical testing	The W17191X likely pathogenic variant in the TTN gene has not been published as pathogenic or benign to our knowledge. This variant 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. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, W17191X 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, the W17191X variant has not been observed in large population cohorts (Lek et al., 2016). In summary, W17191X in the TTN gene is interpreted as a likely pathogenic variant.
Ambry Genetics	RCV002434395	SCV002746067	likely pathogenic	Cardiovascular phenotype	2021-06-24	criteria provided, single submitter	clinical testing	The p.W9767* variant (also known as c.29300G>A), located in coding exon 117 of the TTN gene, results from a G to A substitution at nucleotide position 29300. This changes the amino acid from a tryptophan to a stop codon within coding exon 117. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769413	SCV004608532	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-05-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp18832*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 817543). 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.