rs36210420
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001099404.2(SCN5A):āc.871A>Cā(p.Asn291His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,728 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N291S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.871A>C | p.Asn291His | missense_variant | 7/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.871A>C | p.Asn291His | missense_variant | 7/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.871A>C | p.Asn291His | missense_variant | 7/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.871A>C | p.Asn291His | missense_variant | 7/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152264Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249126Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135148
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461464Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727026
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74394
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 291 of the SCN5A protein (p.Asn291His). This variant is present in population databases (rs36210420, gnomAD 0.002%). This missense change has been observed in individual(s) with torsades de pointes (PMID: 17161064, 30079003). ClinVar contains an entry for this variant (Variation ID: 68051). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2017 | A variant of uncertain significance has been identified in the SCN5A gene. The N291H variant has previously been reported as a polymorphism" in an individual of European ancestry with torsades de pointes (Mank-Seymour et al., 2006). In addition, this variant has been observed in other unrelated individuals referred for cardiac genetic testing at GeneDx; however, segregation data is insufficient to determine the pathogenicity of this variant. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, the N291H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. Furthermore, the N291H variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign." - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces asparagine with histidine at codon 291 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). A functional study has shown that this variant has no significant impact on channel peak current density (PMID: 34930020). This variant has been reported in an individual affected with torsades de pointes (PMID: 17161064) and in another individual noted with atrial fibrillation, long QT syndrome, and syncope from a population screening study (PMID: 34930020). This variant has been identified in 3/280536 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 | Color Diagnostics, LLC DBA Color Health | Mar 10, 2023 | This missense variant replaces asparagine with histidine at codon 291 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). A functional study has shown that this variant has no significant impact on channel peak current density (PMID: 34930020). This variant has been reported in an individual affected with torsades de pointes (PMID: 17161064) and in another individual noted with atrial fibrillation, long QT syndrome, and syncope from a population screening study (PMID: 34930020). This variant has been identified in 3/280536 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2020 | The c.871A>C (p.N291H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a A to C substitution at nucleotide position 871, causing the asparagine (N) at amino acid position 291 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Torsades de pointes Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with torsades de pointes in the following publications (PMID:17161064). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at