ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.10303+2T>C (rs371596417)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459587 SCV000542520 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-01-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 44 of the TTN gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. 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 (rs371596417, ExAC 0.002%). This variant has been observed in combination with another TTN variant in an individual affected with muscle weakness and limb contractures and has been observed in the heterozygous state in an individual with dilated cardiomyopathy (PMID: 29691892, 29892087). ClinVar contains an entry for this variant (Variation ID: 404786). 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 RCV000619220 SCV000737081 likely pathogenic Cardiovascular phenotype 2016-04-02 criteria provided, single submitter clinical testing The c.10165+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 42 in the TTN gene. Exon 42 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 has been reported as c.10303+2T>C in a dilated cardiomyopathy (DCM) cohort with limited clinical details (Halliday BP et al. Lancet, 2019 01;393:61-73). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. <span style="font-family:arial,sans-serif; font-size:10pt">While loss of function variants in TTN are present in 1-3% of the general population, truncating variants (a category that includes canonical splice site variants) in the A-band are the most common cause of dilated cardiomyopathy (DCM) <span style="font-family:arial,sans-serif; font-size:10pt">(Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6<span style="font-family:arial,sans-serif; font-size:10pt">). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (<span style="font-family:arial,sans-serif; font-size:10pt">Schafer S et al. Nat. Genet., 2017 01;49:46-53<span style="font-family:arial,sans-serif; font-size:10pt">). As such, this alteration is classified as likely pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000733858 SCV000861960 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing

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