ClinVar Genomic variation as it relates to human health

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)

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.

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.

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.

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.

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.

The TNNT2 c.230C>T variant is predicted to result in the amino acid substitution p.Pro77Leu. This variant has been reported in an individual diagnosed with hypertrophic cardiomyopathy after sudden cardiac death (Varnava et al. 2001. PubMed ID: 11560853). This variant, also described as p.Pro87Leu, has also been reported in two members of a family with left ventricular noncompaction cardiomyopathy (Hoedemaekers et al. 2010. PubMed ID: 20530761). An in vitro reporter assay did not demonstrate a significant difference between this variant and wildtype (Figure 4G, Pettinato et al. 2020. PubMed ID: 33025817). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD, and has been consistently interpreted as uncertain by several laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/43619/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.