Submissions for variant NM_001276345.2(TNNT2):c.136G>C (p.Ala46Pro)

gnomAD frequency: 0.00001  dbSNP: rs397516447

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036556	SCV000060211	uncertain significance	not specified	2011-02-10	criteria provided, single submitter	clinical testing	The Ala36Pro variant has not been reported in the literature. It has been detec ted by our laboratory in one Asian patient with HCM secondary to Pompe disease. It should be noted that this lab has only sequenced the TNNT2 in 162 Asian indi viduals and no Asian healthy controls. In addition, healthy control information is unavailable from either public databases or scientific literature, such that the full spectrum of benign variation has not yet been defined for this populati on. Future analysis could reveal that the Ala36Pro variant is common and therefo re unlikely to be pathogenic. In addition, alanine (Ala) at position 36 is locat ed in a less well conserved part of the TNNT2 protein, which may indicate that a change would be tolerated. In summary, the clinical significance of this varia nt cannot be determined without further studies.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001089634	SCV001245112	uncertain significance	Hypertrophic cardiomyopathy	2018-04-18	criteria provided, single submitter	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
Invitae	RCV001243568	SCV001416736	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2022-07-08	criteria provided, single submitter	clinical testing	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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 30565988, 33025817). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 43612). This variant is also known as A46P. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397516447, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 36 of the TNNT2 protein (p.Ala36Pro).
New York Genome Center	RCV001243568	SCV002764354	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-08-20	criteria provided, single submitter	clinical testing	The c.136G>C (p.Ala46Pro) variant identified in the TNNT2 gene substitutes a moderately conserved Alanine for Proline at amino acid 46/299 (exon6/17). This variant is found with low frequency in gnomAD(v3.1.1) (6 heterozygotes, 0 homozygotes; allele frequency:3.94e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.298) and Benign (REVEL; score:0.423) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:43612) and has been reported in an individual in the literature with Hypertrophic Cardiomyopathy (listed as c.106G>C, p.Ala36Pro as annotated from transcript NM_001001430.2; [Supp Table S1B,PMID:27532257]). This variant is not within a mapped domain of TNNT2, but is located within a region of compositional bias of acid residues (UniProtKB:P45379). The c.136G>C (p.Ala46Pro) variant identified in the TNNT2 gene is reported as a Variant of Uncertain Significance.
GeneDx	RCV003151739	SCV003840881	uncertain significance	not provided	2023-03-13	criteria provided, single submitter	clinical testing	Identified in a patient with hypertrophic cardiomyopathy (HCM) in published literature (Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest normal protein function (Pettinato et al., 2020); This variant is associated with the following publications: (PMID: 30645170, 30565988, 33025817, 27532257)
Genome-Nilou Lab	RCV003450664	SCV004182630	uncertain significance	Dilated cardiomyopathy 1D	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450665	SCV004182741	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450663	SCV004182852	uncertain significance	Hypertrophic cardiomyopathy 2	2023-11-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996230	SCV004821984	uncertain significance	Cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 36 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study showed similar transcript expression as WT controls (PMID: 33025817). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 8/251454 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	RCV004018794	SCV005036908	likely benign	Cardiovascular phenotype	2023-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Blueprint Genetics	RCV000157535	SCV000207281	likely benign	Primary familial hypertrophic cardiomyopathy	2014-10-30	no assertion criteria provided	clinical testing