ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.803A>T (p.Lys268Ile) (rs397516482)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036618 SCV000060273 uncertain significance not specified 2012-02-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Lys258Ile v ariants has not been reported in the literature but has been identified in 3 ind ividuals with HCM out of over 2,000 Caucasian probands tested by our laboroatory . Computational analyses (biochemical amino acid properties, conservation, PolyP hen2, SIFT) suggest that the Lys258Ile variant may impact the protein. However, this information is not predictive enough to determine pathogenicity. In summary , although this data supports that this variant may be pathogenic, additional st udies are needed to fully assess its clinical significance.
GeneDx RCV000590304 SCV000209262 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing The K258I variant in the TNNT2 gene has been published as a variant of uncertain significance in an individual with early onset HCM and a family history of disease, however no clinical details or segregation data was provided (reported as c.794 A>T, K265I, using alternate nomenclature) (Rubattu et al., 2016). It was also reported in an individual diagnosed with HCM who harbored five additional cardiogenetic variants (reported as c.755 A>T, K252I, using alternate nomenclature) (Bottillo et al., 2016). Additionally, K258I was reported as a variant of uncertain significance in two individuals in a HCM cohort, although no clinical or segregation data was provided and it is unknown if there were other co-occurring variants (Walsh et al., 2017).This variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant. The K258I 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 and this substitution occurs at a position that is conserved across species. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether the K258I variant in the TNNT2 gene is pathogenic or rare benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590304 SCV000697569 uncertain significance not provided 2017-03-28 criteria provided, single submitter clinical testing Variant summary: The TNNT2 c.773A>T (p.Lys258Ile) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121412 control chromosomes. The variant has been reported in the literature, without strong evidence for causality. One internally tested patient (25 y.o. at testing) carries this variant and MYBPC3 c.1750G>C/p.Gly584Arg (pathogenic). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627132 SCV000747946 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-06-26 criteria provided, single submitter clinical testing
Invitae RCV000646072 SCV000767829 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 258 of the TNNT2 protein (p.Lys258Ile). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 27483260, 26656175, 27532257, Invitae). This variant is also known as c.A775T, p.Lys252Ile, c.794C>T and p.Lys265Ile in the literature. ClinVar contains an entry for this variant (Variation ID: 43670). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768715 SCV000900085 uncertain significance Cardiomyopathy 2016-08-10 criteria provided, single submitter clinical testing

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