rs121908551
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000334.4(SCN4A):c.3877G>A(p.Val1293Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,152 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1293L) 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.3877G>A | p.Val1293Ile | missense_variant | 21/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.3877G>A | p.Val1293Ile | missense_variant | 21/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000891 AC: 13AN: 1458950Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 725474
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 05, 2022 | PP1, PP3, PM2, PS3, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 05, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 08, 2023 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with paramyotonia congenita. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9660885, 30611854) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | SCN4A: PP1:Strong, PM1, PM2, PS4:Moderate, PP3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2023 | Reported previously in patients with mild to moderate myotonia and diagnoses of sodium channel myotonia and paramyotonia congenita with onset in the third decade; however, no further clinical or segregation information was provided (Farinato et al., 2019); Published functional studies indicate V1293I alters the voltage-dependent gating behavior of SCN4A (Green et al., 1998; Farinato et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16193245, 29606556, 24939454, 28877545, 21221019, 16786525, 27486940, 28325641, 28662944, 32849172, 32660787, 8580427, 9660885, 30611854, 33263785, 11744749, 23771340, 24136861, 21387378) - |
Paramyotonia congenita of Von Eulenburg Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 23, 1995 | - - |
Hyperkalemic periodic paralysis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1293 of the SCN4A protein (p.Val1293Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant paramyotonia congenita and myotonia congenita (PMID: 8580427, 23771340, 24939454, 27486940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5909). 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: 9660885, 11744749). For these reasons, this variant has been classified as Pathogenic. - |
SCN4A-related disorder Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at