Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000040534 | SCV000064225 | uncertain significance | not specified | 2012-05-01 | criteria provided, single submitter | clinical testing | The Asp20190Asn variant (TTN) has not been reported in the literature nor previo usly identified by our laboratory. It was absent from >3,000 European American individuals sequenced by the NHLBI exome sequencing project (http://evs.gs.washi ngton.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to establish this with confidence. Computational analyses (biochem ical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, additional information is needed to fu lly assess the clinical significance of the Asp20190Asn variant. |
Gene |
RCV000766762 | SCV000590189 | uncertain significance | not provided | 2017-05-24 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the TTN gene. The D21117N variant, also denoted as D20190N due to the use of an alternate transcript, has been reported in a 16 year-old Caucasian male with a clinical diagnosis of DCM, no skeletal myopathy, and no family history of DCM (Pugh et al., 2014); however, this individual harbored additional cardiogenetic variants and no segregation studies were described. Nevertheless, the D21117N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D21117N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, this substitution occurs at a position where only amino acids with similar properties to Aspartic acid are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, although D21117N is located in the A-band region of titin, the majority of pathogenic variants in the TTN gene associated with DCM are truncating variants in the A-band region of titin (Herman et al., 2012). Additionally, this variant is also classified as a variant of uncertain significance in ClinVar by another clinical laboratory (ClinVar SCV000064225.4; Landrum et al., 2016). |