rs757302500
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_001099404.2(SCN5A):c.2570G>A(p.Gly857Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging 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. G857S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.2570G>A | p.Gly857Asp | missense_variant | 16/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.2570G>A | p.Gly857Asp | missense_variant | 16/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2570G>A | p.Gly857Asp | missense_variant | 16/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.2570G>A | p.Gly857Asp | missense_variant | 16/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251366Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461892Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 01, 2023 | This missense variant replaces glycine with aspartic acid at codon 857 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 SCN5A-related disorders in the literature. This variant has been identified in 3/251366 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces glycine with aspartic acid at codon 857 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 SCN5A-related disorders in the literature. This variant has been identified in 3/251366 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 16, 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. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 857 of the SCN5A protein (p.Gly857Asp). This variant is present in population databases (rs757302500, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 406414). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 31, 2019 | The p.G857D variant (also known as c.2570G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2570. The glycine at codon 857 is replaced by aspartic acid, an amino acid with similar properties, and is located in the transmembrane DII-S5 domain. 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