Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000040838 | SCV000064529 | uncertain significance | not specified | 2012-12-12 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Ala29528Thr var iant in TTN has not been reported in the literature, but has been identified by our laboratory in 2 Caucasian individuals with DCM (including this individual). Both individuals also carried likely disease-causing variants in TTN, 1 of which was likely on the same copy of the gene (in cis). In addition, this variant has been identified in 2/8246 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Alani ne (Ala) at position 29528 is conserved in mammals and in evolutionarily distant species down to fish, though the change to threonine (Thr) is present in medaka . Additional computational analyses (biochemical amino acid properties, AlignGVG D, PolyPhen2, and SIFT) do not provide strong support for or against and impact to the protein. In summary, although collectively this information supports that the Ala29528Thr variant may be benign, additional studies are needed to fully a ssess its clinical significance. |
| Gene |
RCV000767014 | SCV000620149 | uncertain significance | not provided | 2017-08-11 | criteria provided, single submitter | clinical testing | The A29528T variant has been reported in one individual with dilated cardiomyopathy; however, this individual harbored additional cardiogenetic variants and segregation data was not provided (Pugh et al., 2014). Additionally, A29528T was reported in an individual with unexplained sudden death, however, detailed clinical information and segregation data was not provided (Sanchez et al., 2016). The A29528T variant is observed in 6/66,468 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Most reported pathogenic variants in the TTN gene are truncating/loss-of-function. However, this variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals, and is located in the A-band of the titin protein, where the majority of pathogenic truncating variants have been reported. In silico analysis predicts this variant is probably damaging to the protein structure/function. |
| Invitae | RCV000643268 | SCV000764955 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2017-08-31 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002504916 | SCV002814000 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 | 2021-07-20 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002514155 | SCV003681478 | likely benign | Inborn genetic diseases | 2021-11-09 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Revvity Omics, |
RCV000767014 | SCV003820120 | uncertain significance | not provided | 2020-03-25 | criteria provided, single submitter | clinical testing |