Submissions for variant NM_001276345.2(TNNT2):c.412G>A (p.Glu138Lys)

gnomAD frequency: 0.00001  dbSNP: rs730881100

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159289	SCV000209235	uncertain significance	not provided	2020-01-28	criteria provided, single submitter	clinical testing	Reported in association with HCM (also reported as E138K using alternate nomenclature); at least two individuals were reported to also harbor variants in the MYH7 gene (Liu et al., 2013; Zou et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23283745, 23711808)
PreventionGenetics, part of Exact Sciences	RCV004528900	SCV004107772	uncertain significance	TNNT2-related disorder	2023-05-19	criteria provided, single submitter	clinical testing	The TNNT2 c.382G>A variant is predicted to result in the amino acid substitution p.Glu128Lys. This variant was reported in three individuals with hypertrophic cardiomyopathy; however, all three individuals harbored an additional variant in genes associated with cardiomyopathy (described as E138K with an alternate transcript NM_000364, Zou et al. 2013. PubMed ID: 23283745; Liu et al. 2013. PubMed ID: 23711808). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-201333503-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome-Nilou Lab	RCV003453222	SCV004181422	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453223	SCV004181423	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453221	SCV004181424	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
Invitae	RCV003765001	SCV004569179	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-03-01	criteria provided, single submitter	clinical testing	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 128 of the TNNT2 protein (p.Glu128Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23283745, 23711808). This variant is also known as c.412G>A (p.E138K). ClinVar contains an entry for this variant (Variation ID: 181616). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
All of Us Research Program, National Institutes of Health	RCV003998389	SCV004839991	uncertain significance	Cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 128 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy who carried a second variant in the MYBPC3 gene (c.2792+12C>T) (PMID: 23711808). This variant has been identified in 2/249434 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.