rs199473071
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000335.5(SCN5A):c.674G>A(p.Arg225Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,609,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_000335.5 | c.674G>A | p.Arg225Gln | missense_variant | 6/28 | ENST00000423572.7 | |
SCN5A | NM_001099404.2 | c.703+203G>A | intron_variant | ENST00000413689.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000423572.7 | c.674G>A | p.Arg225Gln | missense_variant | 6/28 | 1 | NM_000335.5 | A1 | |
SCN5A | ENST00000413689.6 | c.703+203G>A | intron_variant | 5 | NM_001099404.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000166 AC: 4AN: 241632Hom.: 0 AF XY: 0.0000229 AC XY: 3AN XY: 130896
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1456972Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 6AN XY: 724256
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152300Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74468
ClinVar
Submissions by phenotype
Long QT syndrome 3 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Jun 21, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 17, 2022 | _x000D_ Criteria applied: PM5_STR, PS4_MOD, PS3_SUP, PP3 - |
Brugada syndrome 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical 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 | Jun 12, 2023 | This missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Dilated cardiomyopathy 1E Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Dec 20, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24815523, 24631775, 29728395, 29247119, 33071830, 16922724, 28779003) - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the SCN5A protein (p.Arg225Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT syndrome, Brugada syndrome, dilated cardiomyopathy, or sudden death (PMID: 16922724, 28779003, 29247119, 33071830). ClinVar contains an entry for this variant (Variation ID: 68033). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24815523, 28779003). This variant disrupts the p.Arg225 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12574143, 20031634, 24815523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 23, 2021 | The c.674G>A (p.R225Q) alteration is located in exon 6 (coding exon 5) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 674, causing the arginine (R) at amino acid position 225 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Congenital long QT syndrome 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 Long QT syndrome in the following publications (PMID:16922724). 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