rs1329499714
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_001099404.2(SCN5A):c.2875C>T(p.Leu959Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L959P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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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.2875C>T | p.Leu959Phe | missense_variant | 17/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.2875C>T | p.Leu959Phe | missense_variant | 17/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2875C>T | p.Leu959Phe | missense_variant | 17/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.2875C>T | p.Leu959Phe | missense_variant | 17/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Jan 14, 2022 | This missense variant results in a substitution of leucine with phenylalanine at codon 959 of the SCN5A gene (transcript NM_001099404.1). This variant has been reported in ClinVar (463315) NM_000335.5 (SCN5A):c.2875C>T (p.Leu959Phe). The variant has not occurred in population databases. This position is conserved. In silico functional algorithms agree, predicting it as possibly damaging (PolyPhen) and deleterious (SIFT), but no functional studies were performed to confirm these predictions. The variant has not occurred in the literature associated with the disease. In conclusion, the available evidence is insufficient to determine the pathogenicity of this variant. Therefore, it is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 27, 2017 | This variant identified in the SCN5A gene is located in the interdomain linker DII/DIII region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. In summary, this variant has uncertain impact on SCN5A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with a SCN5A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 959 of the SCN5A protein (p.Leu959Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the linker region between transmembrane domains DII and DIII of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at