ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.826A>G (p.Asn276Asp) (rs4523540)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474789 SCV000541912 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 269 of the TNNT2 protein (p.Asn269Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs4523540, ExAC 0.003%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181647). 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. 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769738 SCV000901160 uncertain significance Cardiomyopathy 2016-04-28 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786229 SCV000924970 uncertain significance not provided 2017-06-12 no assertion criteria provided provider interpretation p.Asn269Asp (c.805A>G; chr1:201328767) in the TNNT2 gene (NM_001001430.2) Given the lack of case data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). To our knowledge, there is no published literature that associates this variant with cardiomyopathy. This variant is present in ClinVar, but has only been submitted by Invitae. Per the test report, "Algorithms developed to predict the e ect of missense changes on protein structure and function (SIFT, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have notcon rmed by published functional studies." The asparagine at codon 269 is moderately conserved across species, as are neighboring amino acids. Another variant at this codon, p.Asn269Ser, is classified as a variant of uncertain significance by 2 labs in ClinVar. A variant at a nearby codon is currently classified as a pathogenic variant by GeneDx; however, it was last reviewed in 2011 and by the ACMG's 2015 criteria, would be called a variant of uncertain significance. The variant was reported online in 2 of 110,230 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 46,523 individuals of European descent (MAF=0.002%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Another variant at this codon is present at relatively high frequency in gnomAD; however, it is a synonymous variant (p.Asn269Asn; MAF=0.01%).

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