rs80338962
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000334.4(SCN4A):c.4774A>G(p.Met1592Val) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1592I) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.4774A>G | p.Met1592Val | missense_variant | 24/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.4774A>G | p.Met1592Val | missense_variant | 24/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 21, 2020 | PS3, PS4_Moderate, PM2, PP1, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2023 | Published functional studies demonstrate that the variant impairs slow inactivation of the sodium channel (Hayward et al., 1999); 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; This variant is associated with the following publications: (PMID: 24943082, 19290024, 24714718, 21404612, 32327288, 1659668, 10227633, 31068157, 21665479, 32849172, 31567646, 29930533, 23801527, 18046642, 20301669) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 21, 2021 | This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple families and individuals with periodic paralysis, including at least one de novo case. This variant is primarily associated with cases presenting with hyperkalemic periodic paralysis (hyperKPP; PMID: 15534250), however rare cases of normokalemic periodic paralysis (normoKPP) are also reported (PMID: 29930533). Assessment of experimental evidence suggests this variant results in abnormal protein function. Patch-clamp studies demonstrate the variant modifies activation of mutant sodium channels (PMID: 9886942). Introduction of this variant in mice produces characteristics of hyperKPP (PMID: 18317596, 21708955, 24714718). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | SCN4A: PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3 - |
Hyperkalemic periodic paralysis Pathogenic:3Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1592 of the SCN4A protein (p.Met1592Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant SCN4A-related conditions (PMID: 1659668, 8242056, 9131651, 18046642, 21665479, 23801527, 24943082). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5897). 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: 24714718). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences | Apr 12, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Paramyotonia congenita/hyperkalemic periodic paralysis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1997 | - - |
Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at