rs1335890539
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_001099404.2(SCN5A):c.4280C>A(p.Ala1427Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 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. A1427S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.4280C>A | p.Ala1427Glu | missense_variant | 24/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.4277C>A | p.Ala1426Glu | missense_variant | 24/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4280C>A | p.Ala1427Glu | missense_variant | 24/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4277C>A | p.Ala1426Glu | missense_variant | 24/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461682Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727148
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 06, 2018 | The p.A1427E variant (also known as c.4280C>A), located in coding exon 23 of the SCN5A gene, results from a C to A substitution at nucleotide position 4280. The alanine at codon 1427 is replaced by glutamic acid, an amino acid with dissimilar properties, and is located in the S5–S6 extracellular linker of domain III. This variant has not been described in the literature to date; however, an alteration involving the same amino acid position, p.A1427S (c.4279G>T), has been reported in a patient from a clinically suspected Brugada syndrome cohort (Kapplinger JD et al. Heart Rhythm, 2010;7:33-46). This amino acid position is highly 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