ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.775G>A (p.Asp259Asn) (rs141805127)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172136 SCV000051078 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000172136 SCV000209260 likely pathogenic not provided 2013-11-14 criteria provided, single submitter clinical testing p.Asp249Asn (GAC>AAC): c.745 G>A in exon 14 of the TNNT2 gene (NM_001001430.1). The Asp249Asn variant in the TNNT2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp249Asn results in a semi-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral polar Asparagine at a position that is conserved in mammals. In silico analysis predicts Asp249Asn is damaging to the protein structure/function. The Asp249Asn variant was not observed with any significant frequency in 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. However, no mutations in nearby residues have been reported in association with cardiomyopathy. With the clinical and molecular information available at this time, we cannot definitively determine if Asp249Asn is a disease-causing mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000466482 SCV000541934 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 249 of the TNNT2 protein (p.Asp249Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs141805127, ExAC 0.02%). This variant has been observed in an individual affected with cardiomyopathy (PMID: 30165862). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000620239 SCV000739979 uncertain significance Cardiovascular phenotype 2019-05-17 criteria provided, single submitter clinical testing Insufficient evidence
Mendelics RCV000986502 SCV001135515 uncertain significance Familial hypertrophic cardiomyopathy 2 2019-05-28 criteria provided, single submitter clinical testing
Color RCV001177367 SCV001341565 uncertain significance Cardiomyopathy 2019-11-22 criteria provided, single submitter clinical testing

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