ClinVar Miner

Submissions for variant NM_133378.4(TTN):c.59644+1G>A (rs758279518)

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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 RCV000414246 SCV000331945 likely pathogenic not provided 2015-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000414246 SCV000491396 likely pathogenic not provided 2016-01-13 criteria provided, single submitter clinical testing Although the c.62425+1 G>A variant has not been reported as a pathogenic variant or as a benign variant to our knowledge, it destroys the canonical splice donor site in intron 268 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, the c.62425+1 G>A variant 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). Multiple other downstream splice site variants in the TTN gene have been reported in HGMD in association with DCM (Stenson et al., 2014), including another variant affecting the same donor site (c.62425+5 G>A). Furthermore, the c.62425+1 G>A variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.62425+1 G>A in the TTN gene is interpreted as a pathogenic variant.
Invitae RCV000821995 SCV000962772 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-02-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 318 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs758279518, ExAC 0.002%). This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 281260). 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). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TTN are known to be pathogenic (PMID: 17444505, 22335739, 23975875, 24395473). 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.
Clinical Genetics Laboratory,Region Ostergotland RCV001175311 SCV001250897 likely pathogenic Dilated cardiomyopathy 1A 2019-10-10 criteria provided, single submitter clinical testing 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). We have confirmed that this variant affects splicing and leads to frame shift. RNA was extracted from heart tissue from a patient with dilated cardiomyopathy, who carried this variant. Sanger sequencing of this RNA showed that the variant resulted in a 50bp deletion, c.59595-c.59644, leading to frame shift.

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