chr3-38608209-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001099404.2(SCN5A):c.940T>C(p.Tyr314His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Y314D) 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.940T>C | p.Tyr314His | missense_variant | 8/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.940T>C | p.Tyr314His | missense_variant | 8/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.940T>C | p.Tyr314His | missense_variant | 8/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.940T>C | p.Tyr314His | missense_variant | 8/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 27
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2017 | In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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, but these predictions have not been confirmed by published functional studies. This variant identified in the SCN5A gene is located in the transmembrane spanning DI-S5/S6 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. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201574). This sequence change replaces tyrosine with histidine at codon 314 of the SCN5A protein (p.Tyr314His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2017 | The Tyr314His variant in the SCN5A gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Tyr314His results in a non-conservative substitution of a neutral, polar Tyrosine residue with a positively charged Histidine residue at a position that is conserved across species. Although in silico analysis predicts Tyr314His is probably benign to the protein structure/function (Adzhubei 2010; Schwarz 2011), other mutations affecting nearby residues (Leu315Pro, Lys317Asn) have been reported in association with Brugada syndrome, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Tyr314His was not observed in approximately 3,000 individuals from European and African American backgrounds. The variant is found in LQT panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at