rs1555863491
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000363.5(TNNI3):c.512C>T(p.Ala171Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A171T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000363.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3 | NM_000363.5 | c.512C>T | p.Ala171Val | missense_variant | 7/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.512C>T | p.Ala171Val | missense_variant | 7/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460504Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726578
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 05, 2017 | In summary, this variant is a novel missense change that affects a residue important for protein function. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Ala171Thr) has been determined to be pathogenic (PMID: 12531876, 15961398, 16288990, 18423659, 27532257). This suggests that the alanine residue is critical for TNNI3 protein function and that other missense substitutions at this position may also be pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TNNI3-related disease. This sequence change replaces alanine with valine at codon 171 of the TNNI3 protein (p.Ala171Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at