rs121908545
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000334.4(SCN4A):c.4343G>T(p.Arg1448Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1448S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.4343G>T | p.Arg1448Leu | missense_variant | 24/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.4343G>T | p.Arg1448Leu | missense_variant | 24/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 06, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 31, 2017 | - - |
Hyperkalemic periodic paralysis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 11, 2022 | 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. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1448 of the SCN4A protein (p.Arg1448Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of paramyotonia congenita (PMID: 18166706; Invitae). ClinVar contains an entry for this variant (Variation ID: 586518). This variant disrupts the p.Arg1448 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1316765, 7809121, 8005599, 16801039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at