rs199473246
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_001099404.2(SCN5A):c.4296G>T(p.Arg1432Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,608 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1432G) 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.4296G>T | p.Arg1432Ser | missense_variant | 24/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.4293G>T | p.Arg1431Ser | missense_variant | 24/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4296G>T | p.Arg1432Ser | missense_variant | 24/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4293G>T | p.Arg1431Ser | missense_variant | 24/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461608Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727104
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 11, 2018 | This sequence change replaces arginine with serine at codon 1432 of the SCN5A protein (p.Arg1432Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Brugada syndrome (Invitae). 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 and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Arg4132Ser and p.Arg4132Gly) in affected individuals suggests that this may be a clinically significant residue (PMID: 28341781, 10727653, 25904541). A different variant (c.4296G>C) giving rise to the same protein effect observed here (p.Arg1432Ser) has been reported in an individual affected with Brugada syndrome (PMID: 28341781) and in an individual affected with long QT syndrome or referred for long QT syndrome clinical genetic testing (PMID: 25904541), indicating that this residue may be critical for 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at