rs199473592
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP2
The NM_001099404.2(SCN5A):āc.3068G>Cā(p.Arg1023Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,604,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1023H) has been classified as Likely benign.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3068G>C | p.Arg1023Pro | missense_variant | 17/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3068G>C | p.Arg1023Pro | missense_variant | 17/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3068G>C | p.Arg1023Pro | missense_variant | 17/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3068G>C | p.Arg1023Pro | missense_variant | 17/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000332 AC: 5AN: 150684Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 247778Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134592
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1454124Hom.: 0 Cov.: 37 AF XY: 0.00000553 AC XY: 4AN XY: 723274
GnomAD4 genome AF: 0.0000332 AC: 5AN: 150684Hom.: 0 Cov.: 32 AF XY: 0.0000408 AC XY: 3AN XY: 73574
ClinVar
Submissions by phenotype
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 11, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2023 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 969680). This missense change has been observed in individual(s) with sudden unexplained infant death (PMID: 30079003). This variant is present in population databases (rs199473592, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1023 of the SCN5A protein (p.Arg1023Pro). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2022 | The p.R1023P variant (also known as c.3068G>C), located in coding exon 16 of the SCN5A gene, results from a G to C substitution at nucleotide position 3068. The arginine at codon 1023 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in a whole exome sequencing cohort and an electronic medical records cohort (Van Driest SL et al. JAMA, 2016 Jan;315:47-57; Ghouse J et al. Genet Med, 2017 05;19:521-528). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 17, 2023 | This missense variant replaces arginine with proline at codon 1023 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/247778 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at