Submissions for variant NM_001276345.2(TNNT2):c.260C>T (p.Pro87Leu)

gnomAD frequency: 0.00002  dbSNP: rs144900708

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036563	SCV000060218	uncertain significance	not specified	2012-10-03	criteria provided, single submitter	clinical testing	The Pro77Leu variant in TNNT2 has been identified in 1 individual with HCM/SCD ( Varnava 2001) as well as in 1/8600 European American chromosomes from a broad po pulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs144900708). Proline (Pro) at position 77 is conserved in mammals and some evolutionarily distant species, but frog and stickleback carry a leucine (L eu; this variant) at this position suggesting that this change may be tolerated. Other computational analyses (biochemical amino acid properties, AlignGVGD, Pol yPhen2, and SIFT) suggest that this variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. Additional s tudies are needed to fully assess the clinical significance of this variant.
Invitae	RCV000646057	SCV000767814	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2022-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 77 of the TNNT2 protein (p.Pro77Leu). This variant is present in population databases (rs144900708, gnomAD 0.02%). This missense change has been observed in individual(s) with TNNT2-related conditions (PMID: 11560853, 20530761). This variant is also known as p.Pro87Leu. ClinVar contains an entry for this variant (Variation ID: 43619). 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. Experimental studies have shown that this missense change does not substantially affect TNNT2 function (PMID: 33025817). 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.
Color Diagnostics, LLC DBA Color Health	RCV001185063	SCV001351204	uncertain significance	Cardiomyopathy	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 77 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy and sudden cardiac death (PMID: 11560853) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 20530761). This variant has been identified in 10/251110 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.
GeneDx	RCV001588848	SCV001822892	uncertain significance	not provided	2020-10-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33025817, 23299917, 19914256, 11560853, 20530761, 25637381)
Fulgent Genetics, Fulgent Genetics	RCV000646057	SCV002784510	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-09-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450670	SCV004181542	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450671	SCV004181543	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450669	SCV004181544	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001185063	SCV004821981	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 77 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy and sudden cardiac death (PMID: 11560853) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 20530761). This variant has been identified in 10/251110 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.
Ambry Genetics	RCV004018795	SCV004968976	uncertain significance	Cardiovascular phenotype	2021-12-07	criteria provided, single submitter	clinical testing	The c.230C>T (p.P77L) alteration is located in exon 8 (coding exon 7) of the TNNT2 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the proline (P) at amino acid position 77 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CSER _CC_NCGL, University of Washington	RCV000148902	SCV000190648	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV001588848	SCV001920415	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001588848	SCV001966473	uncertain significance	not provided		no assertion criteria provided	clinical testing