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

gnomAD frequency: 0.00001  dbSNP: rs397516482

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996231	SCV000060273	uncertain significance	Hypertrophic cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	The p.Lys258Ile variant in TNNT2 has been reported in 8 individuals with hypertrophic cardiomyopathy (HCM; Bottillo 2016 PMID: 26656175, Rubattu 2016 PMID: 27483260, Walsh 2017 PMID: 27532257, Hathaway 2021 PMID: 33673806, LMM Data, Invitae Personal Communication 2023). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43670) and has been identified in 0.0015% (1/68010) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant may impact protein function (Pettinato 2020 PMID: 33025817); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP3.
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	RCV000036618	SCV000697569	uncertain significance	not specified	2024-01-30	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.773A>T (p.Lys258Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-06 in 152150 control chromosomes in gnomAD database (v4.0.0). c.773A>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Botillo_2016, Walsh_2016, Hathaway_2021, Ho_2018, Ko_2018) with limited clinical details. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.The following publications have been ascertained in the context of this evaluation (PMID: 26656175, 33673806, 30297972, 28640247, 27483260, 27532257). ClinVar contains an entry for this variant (Variation ID: 43670). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
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	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 258 of the TNNT2 protein (p.Lys258Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26656175, 27483260, 27532257; Invitae). This variant is also known as c.A775T, p.Lys252Ile, c.794C>T and p.Lys265Ile. ClinVar contains an entry for this variant (Variation ID: 43670). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768715	SCV000900085	likely pathogenic	Cardiomyopathy	2023-05-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162316	SCV003866017	uncertain significance	Cardiovascular phenotype	2020-03-09	criteria provided, single submitter	clinical testing	The c.773A>T (p.K258I) alteration is located in exon 14 (coding exon 13) of the TNNT2 gene. This alteration results from a A to T substitution at nucleotide position 773, causing the lysine (K) at amino acid position 258 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000768715	SCV004359922	likely pathogenic	Cardiomyopathy	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 258 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using human induced pluripotent stem cells has shown that this variant may impact TNNT2 protein function in manner consistent with hypertrophic cardiomyopathy (PMID: 33025817); the clinical relevance of this observation is not known. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 26656175, 27483260, 27532257, 28640247, 29875424, 33495596, 33495597, 33673806; communication with an external laboratory; ClinVar SCV000060273.6, SCV000767829.7, SCV000209262.13). One of these individuals also carried a pathogenic variant in a different gene associated with cardiomyopathy (SCV000209262.13). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003996231	SCV004830753	likely pathogenic	Hypertrophic cardiomyopathy	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 258 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using human induced pluripotent stem cells has shown that this variant may impact TNNT2 protein function in manner consistent with hypertrophic cardiomyopathy (PMID: 33025817); the clinical relevance of this observation is not known. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 26656175, 27483260, 27532257, 28640247, 29875424, 33495596, 33495597, 33673806; communication with an external laboratory; ClinVar SCV000060273.6, SCV000767829.7, SCV000209262.13). One of these individuals also carried a pathogenic variant in a different gene associated with cardiomyopathy (SCV000209262.13). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.