15-73343504-C-A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_005477.3(HCN4):c.1090G>T(p.Asp364Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D364N) has been classified as Likely benign.
Frequency
Consequence
NM_005477.3 missense
Scores
Clinical Significance
Conservation
Publications
- sick sinus syndrome 2, autosomal dominantInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- Brugada syndrome 8Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- familial sick sinus syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: LIMITED Submitted by: ClinGen
- Brugada syndrome 1Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727246 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74328 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 Uncertain:1
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Brugada syndrome 8 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 364 of the HCN4 protein (p.Asp364Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 519419). 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 not expected to disrupt HCN4 protein function. 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. -
Cardiovascular phenotype Uncertain:1
The p.D364Y variant (also known as c.1090G>T), located in coding exon 2 of the HCN4 gene, results from a G to T substitution at nucleotide position 1090. The aspartic acid at codon 364 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at