Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000159195 | SCV000209141 | likely pathogenic | not provided | 2013-09-11 | criteria provided, single submitter | clinical testing | This variant is denoted p.Asp88Asn (GAC>AAC): c.262 G>A in exon 4 of the TNNC1 gene (NM_003280.2). The Asp88Asn variant in the TNNC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp88Asn results in a semi-conservative amino acid substitution of one negatively charged Aspartic acid with a neutral, polar Asparagine at a position that is conserved across species. In silico algorithms are not consistent in their predictions but at least two concur Asp88Asn is damaging to the protein structure/function. Mutations in nearby residues (Asp75Tyr, Cys84Tyr, Met103Ile) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Asp88Asn variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Asp88Asn is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The pathogenic role for this variant would be further supported if it co-segregates with a cardiomyopathy phenotype in this family. The variant is found in DCM panel(s). |
Invitae | RCV000647102 | SCV000768889 | uncertain significance | Dilated cardiomyopathy 1Z; Hypertrophic cardiomyopathy 13 | 2019-10-27 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TNNC1-related disease. ClinVar contains an entry for this variant (Variation ID: 181563). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 88 of the TNNC1 protein (p.Asp88Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. |