ClinVar Miner

Submissions for variant NM_133379.5(TTN):c.1800+1G>A (rs397517497)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039959 SCV000063650 likely pathogenic Primary dilated cardiomyopathy 2012-10-17 criteria provided, single submitter clinical testing The 1800+1G>A variant in TTN has not been reported in the literature but has bee n identified in a child with DCM previously tested by our laboratory (LMM unpubl ished data). This variant has not been identified by large and broad European Am erican and African American populations screened by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS), which is consistent with a pathogenic role. However, we cannot exclude that it may be common in other populations. Th is variant occurs in the invariant region (+/- 1, 2) of the splice consensus seq uence and is predicted to cause altered splicing leading to an abnormal or absen t protein. Heterozygous loss of function of the TTN gene is strongly associated with DCM (Herman 2012). In summary, this variant is likely pathogenic, though ad ditional studies are required to fully establish its clinical significance.
GeneDx RCV000184208 SCV000236830 likely pathogenic not provided 2014-07-08 criteria provided, single submitter clinical testing c.1800+1 G>A: IVS11+1 G>A in intron 11 of the TTN gene (NM_001256850.1). Although the c.1800+1 G>A variant has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this variant destroys the canonical splice donor site in intron 11 and is predicted to cause abnormal gene splicing. However, other truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman et al., 2012). Furthermore, c.1800+1 G>A is not located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman et al., 2012).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000503453 SCV000588372 likely pathogenic Muscular dystrophy 2017-06-18 criteria provided, single submitter clinical testing
Invitae RCV000707086 SCV000836167 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-05-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a 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 (rs397517497, ExAC 0.05%). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 46689). This variant is located in the Z 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.

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