Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001276345.2(TNNT2):c.720-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,668 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 1-201361373-C-A is Benign according to our data. Variant chr1-201361373-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2, Benign=2}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000208 (304/1461358) while in subpopulation MID AF= 0.00295 (17/5766). AF 95% confidence interval is 0.00188. There are 2 homozygotes in gnomad4_exome. There are 155 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
Likely benign, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
May 07, 2015
c.690-4G>T in intron 13 of TNNT2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 14/66732 European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201753429). -
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Aug 20, 2018
Variant summary: TNNT2 c.690-4G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00015 in 277154 control chromosomes in the gnomAD database, including 1 homozygote. Though it is relatively frequent, this frequency is not higher than expected for a pathogenic variant in TNNT2 causing Cardiomyopathy (0.00015 vs 0.00018). c.690-4G>T has been reported in the literature in individuals affected with Cardiomyopathy. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations, including VUS (1x) and likely benign (2x). An internal sample with this variant also carried a pathogenic mutation in MYBPC3 variant (c.2373dupG), suggesting the variant of interest is likely not the cause of disease in this case and may be in the benign spectrum. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 25, 2018
- -
Benign, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Jun 06, 2019
- -
not provided Benign:2
Benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 03, 2015
- -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Dec 01, 2023
TNNT2: BP4, BS1 -
Sudden cardiac death Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Blueprint Genetics
Oct 22, 2015
- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 18, 2020
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. -
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 20, 2024
- -
TNNT2-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Feb 22, 2019
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -