rs1060501716
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_006514.4(SCN10A):c.1730T>A(p.Leu577His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,545,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. L577I) has been classified as Likely benign.
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.1730T>A | p.Leu577His | missense_variant | 12/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.1730T>A | p.Leu577His | missense_variant | 12/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.1757T>A | p.Leu586His | missense_variant | 12/28 | ||||
SCN10A | ENST00000643924.1 | c.1730T>A | p.Leu577His | missense_variant | 11/27 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151922Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000202 AC: 4AN: 198358Hom.: 0 AF XY: 0.00000937 AC XY: 1AN XY: 106690
GnomAD4 exome AF: 0.0000136 AC: 19AN: 1393496Hom.: 0 Cov.: 30 AF XY: 0.0000145 AC XY: 10AN XY: 688628
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151922Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74182
ClinVar
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces leucine with histidine at codon 577 of the SCN10A protein (p.Leu577His). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 | Apr 17, 2023 | The p.L577H variant (also known as c.1730T>A), located in coding exon 11 of the SCN10A gene, results from a T to A substitution at nucleotide position 1730. The leucine at codon 577 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at