ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.81532G>T (p.Glu27178Ter)

dbSNP: rs397517721
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040667 SCV000064358 likely pathogenic Primary dilated cardiomyopathy 2017-01-16 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290682 SCV001478814 likely pathogenic Primary familial dilated cardiomyopathy 2021-01-28 criteria provided, single submitter clinical testing Variant summary: TTN c.73828G>T (p.Glu24610X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is located in exon 275 with high expression in heart (https://www.cardiodb.org/titin/). Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (PMID: 22335739, PMID: 24503780) and/or are located in an exon that is highly expressed in the heart (PMID: 25589632). The variant was absent in 248196 control chromosomes (gnomAD). To our knowledge, no occurrence of c.73828G>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001378905 SCV001576598 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu27178*) 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 premature translational stop signal has been observed in individual(s) with pediatric dilated cardiomyopathy and/or TTN-related conditions (PMID: 21520333, 34935411). This variant is also known as p.Glu24610*. ClinVar contains an entry for this variant (Variation ID: 47397). 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.

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