Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
RCV000184208 | SCV000236830 | uncertain significance | not provided | 2022-05-31 | criteria provided, single submitter | clinical testing | Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Reported in an abstract, as a heterozygous variant in a child with high serum creatine kinase, mild motor weakness, mild sural hypertrophy, and muscle biopsy indicating a dystrophic process with reduced alpha-dystrophin staining, who also had a homozygous variant in the ISPD gene (Aksoy et al., 2019) |
Genomic Research Center, |
RCV000503453 | SCV000588372 | likely pathogenic | Muscular dystrophy | 2017-06-18 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000707086 | SCV000836167 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-11-30 | 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 truncated or disrupted TTN protein. This variant is present in population databases (rs397517497, gnomAD 0.05%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy and/or distal myopathy (PMID: 34553419, 34935411). ClinVar contains an entry for this variant (Variation ID: 46689). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the Z band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). 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. |