rs121908556
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000334.4(SCN4A):c.2023C>T(p.Arg675Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,608,322 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R675G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.2023C>T | p.Arg675Trp | missense_variant | 13/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.2023C>T | p.Arg675Trp | missense_variant | 13/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 243902Hom.: 0 AF XY: 0.0000226 AC XY: 3AN XY: 132538
GnomAD4 exome AF: 0.00000481 AC: 7AN: 1456266Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4AN XY: 723622
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74282
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 08, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 21, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (R675G) and (R675Q) have been reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31708864, 19201608, 19052238, 29606556, 22016737, 32962503, 24772081, 20301669, 29930533, 22926674, 15596759) - |
Hyperkalemic periodic paralysis Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 675 of the SCN4A protein (p.Arg675Trp). This variant is present in population databases (rs121908556, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant SCN4A-related conditions (PMID: 15596759, 29606556). ClinVar contains an entry for this variant (Variation ID: 5902). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN4A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 19052238). This variant disrupts the p.Arg675 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15596759, 19052238, 22926674). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Paramyotonia congenita of Von Eulenburg Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 01, 2020 | - - |
Normokalemic periodic paralysis, potassium-sensitive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 14, 2004 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at