ClinVar Miner

Submissions for variant NM_001256850.1(TTN):c.39893-1G>A (rs749705939)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184214 SCV000236836 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing The c.39893-1 G>A pathogenic variant in the TTN gene has been reported in a patient with centronuclear myopathy and a normal cardiac evaluation who also harbored c.35635 G>C in the TTN gene in trans (Ceyhan-Birsoy et al., 2013). The c.39893-1 G>A variant was maternally inherited from a mother with subclinical cardiac and skeletal myopathies (Ceyhan-Birsoy et al., 2013). This variant has also been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to segregate with disease in multiple affected individuals from two unrelated families. The c.39893-1 G>A variant destroys the canonical splice acceptor site in intron 192 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. Immunofluorescence analysis on a muscle biopsy from a patient harboring c.39893-1 G>A demonstrated truncated protein product (Ceyhan-Birsoy et al., 2013). 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 c.39893-1 G>A 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 (Rahual C. Deo, 2016; Schafer et al., 2017). Furthermore, the c.39893-1 G>A variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000184214 SCV000338272 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing
Invitae RCV000476723 SCV000542917 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-10-30 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 242 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 (rs749705939, ExAC 0.003%). This variant has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 23975875). 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: 202368). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23975875). 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). For these reasons, this variant has been classified as Pathogenic.
GenomeConnect, ClinGen RCV000509547 SCV000607336 not provided Cardiomyopathy no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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