ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter) (rs727504198)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000760496 SCV000226712 uncertain significance not provided 2015-12-22 criteria provided, single submitter clinical testing
Invitae RCV000560235 SCV000643133 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-04-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Glu13655*). 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 (ExAC no frequency). This variant has been observed in individual(s) with clinical features of congenital myopathy (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167788). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000618763 SCV000737324 likely pathogenic Cardiovascular phenotype 2019-09-13 criteria provided, single submitter clinical testing The p.E4590* variant (also known as c.13768G>T), located in coding exon 52 of the TTN gene, results from a G to T substitution at nucleotide position 13768. This changes the amino acid from a glutamic acid to a stop codon within coding exon 52. This exon is located in the I-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.
GeneDx RCV000760496 SCV000890386 likely pathogenic not provided 2018-03-30 criteria provided, single submitter clinical testing The E12014X likely pathogenic variant in the TTN gene has not been published as pathogenic or benign to our knowledge. This variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). The E12014X 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. Truncating TTN variants have been reported in approximately 3% of control alleles, and the majority of truncating pathogenic variants associated with DCM have been reported in the A-band (Herman et al., 2012). However, the E12014X variant is located in one of the constitutive exons in the distal I-band region, and recent studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are also significantly associated with DCM (Schafer et al., 2017; Rahual C. Deo, 2016).In summary, E12014X in the TTN gene is interpreted as a likely pathogenic variant.

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