rs987266626
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_001099404.2(SCN5A):c.2390G>T(p.Gly797Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,588 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G797A) 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 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.2390G>T | p.Gly797Val | missense_variant | 15/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.2390G>T | p.Gly797Val | missense_variant | 15/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2390G>T | p.Gly797Val | missense_variant | 15/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.2390G>T | p.Gly797Val | missense_variant | 15/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461588Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727070
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This missense variant replaces glycine with valine at codon 797 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 been reported in one family affected with long QT Syndrome in the literature (PMID: 26669661). This variant has not been identified 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 | Aug 15, 2023 | This missense variant replaces glycine with valine at codon 797 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 been reported in one family affected with long QT Syndrome in the literature (PMID: 26669661). This variant has not been identified 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 | Sep 17, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 797 of the SCN5A protein (p.Gly797Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 26669661). ClinVar contains an entry for this variant (Variation ID: 519096). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2016 | The p.G797V variant (also known as c.2390G>T), located in coding exon 14 of the SCN5A gene, results from a G to T substitution at nucleotide position 2390. The glycine at codon 797 is replaced by valine, an amino acid with dissimilar properties. This variant was observed in a cohort reported to have long QT syndrome; however, clinical details were limited (Itoh H et al. Eur J Hum Genet. 2015:1-7). The variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6380 samples (12760 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species, and the alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. As supporting evidence is limited, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at