19-55154172-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_000363.5(TNNI3):c.407G>A(p.Arg136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000363.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248592Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134966
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460818Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726706
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 7 Pathogenic:2
The c.407G>A, p.Arg136Gln variant has 0.0004% allele frequency in the gnomAD database (1 out of 248,592 heterozygous alleles), indicating this is a rare allele. This sequence change has been observed in individuals affected with hypertrophic cardiomyopathy [PMID: 28356264; PMID:27532257; PMID: 24510615; PMID: 22765922; PMID: 20624503]. In silico tools(SIFT, PolyPhen-2, Align-GVGD, REVEL, and CADD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Based on available evidence this variant has been classified as Likely Pathogenic. -
PS4_Str -
not provided Pathogenic:2
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23140321, 27532257, 20624503, 22765922, 24510615, 34426522, 33336002, 33193569, 33087929, 37652022, 25132132, 38880420, 30297972, 35176171, 24793961, 20800588) -
- -
Hypertrophic cardiomyopathy Pathogenic:1Uncertain:1
This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 24510615, 24793961, 25132132, 27532257, 30297972, 35176171). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 20624503). This variant is present in 1/248592 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the TNNI3 protein (p.Arg136Gln). This variant is present in population databases (rs730881069, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20624503, 22765922, 24510615, 27532257, 28356264; Invitae). ClinVar contains an entry for this variant (Variation ID: 181576). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
TNNI3-related disorder Pathogenic:1
The c.407G>A (p.Arg136Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy (PMID: 20624503, 27532257, 33336002, 33087929, 34426522, 37652022). The c.407G>A (p.Arg136Gln) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.0002% (3/1460818) and thus is presumed to be rare. Based on the available evidence, c.407G>A (p.Arg136Gln) is classified as Likely Pathogenic. -
Cardiomyopathy Pathogenic:1
- -
Cardiovascular phenotype Pathogenic:1
The p.R136Q variant (also known as c.407G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 407. The arginine at codon 136 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (Millat G et al. Eur J Med Genet. 2010 Jul;53(5):261-7; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; T; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Osadnik T et al. Kardiol Pol. 2022 Feb;80(4):482-484). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic for autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at