rs199473046
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_001099404.2(SCN5A):c.101G>A(p.Arg34His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R34C) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.101G>A | p.Arg34His | missense_variant | 2/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.101G>A | p.Arg34His | missense_variant | 2/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.101G>A | p.Arg34His | missense_variant | 2/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.101G>A | p.Arg34His | missense_variant | 2/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000442 AC: 11AN: 248636Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 134986
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461198Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726906
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74312
ClinVar
Submissions by phenotype
not provided Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 34 of the SCN5A protein (p.Arg34His). This variant is present in population databases (rs199473046, gnomAD 0.02%). This missense change has been observed in individual(s) with complete heart block or dilated cardiomyopathy (PMID: 28018021, 32880476). ClinVar contains an entry for this variant (Variation ID: 67627). 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 tolerated. 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 | Oct 29, 2020 | Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#67627; Landrum et al., 2016); 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: 32880476, 28018021, 20129283, 19841300) - |
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:19841300;PMID:20129283). - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 12, 2023 | This missense variant replaces arginine with histidine at codon 34 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with complete heart block (PMID: 28018021), in an individual affected with dilated cardiomyopathy (PMID: 32880476), as well as in two unaffected control subjects (PMID:19841300, 20129283). This variant has been identified in 11/248636 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 | Feb 05, 2024 | This missense variant replaces arginine with histidine at codon 34 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with complete heart block (PMID: 28018021), in an individual affected with dilated cardiomyopathy (PMID: 32880476), as well as in two unaffected control subjects (PMID:19841300, 20129283). This variant has been identified in 11/248636 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. - |
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Apr 24, 2018 | - - |
SCN5A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 19, 2024 | The SCN5A c.101G>A variant is predicted to result in the amino acid substitution p.Arg34His. This variant was reported in an individual with dilated cardiomyopathy (Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). This variant was also reported in the compound heterozygous state in an individual with congenital complete heart block. The apparently unaffected mother was heterozygous for the c.101G>A variant (Thongnak et al. 2016. PubMed ID: 28018021). This variant was documented in at least one control individual (Table S1, Kapa et al. 2009. PubMed ID: 19841300; Kapplinger et al. 2010. PubMed ID: 20129283). This variant is reported in 0.019% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 17, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2021 | The c.101G>A (p.R34H) alteration is located in exon 2 (coding exon 1) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 101, causing the arginine (R) at amino acid position 34 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at