rs121908548
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000334.4(SCN4A):c.4765G>A(p.Val1589Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,884 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 (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SCN4A
NM_000334.4 missense
NM_000334.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
SCN4A (HGNC:10591): (sodium voltage-gated channel alpha subunit 4) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a transmembrane_region Helical; Name=S6 of repeat IV (size 22) in uniprot entity SCN4A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000334.4
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
?
Variant 17-63941517-C-T is Pathogenic according to our data. Variant chr17-63941517-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63941517-C-T is described in Lovd as [Pathogenic]. Variant chr17-63941517-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.4765G>A | p.Val1589Met | missense_variant | 24/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.4765G>A | p.Val1589Met | missense_variant | 24/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 727242
GnomAD4 exome
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6
AN:
1461884
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Cov.:
34
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3
AN XY:
727242
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2021 | Multiple in vitro and in vivo functional studies show that V1589M alters properties of channel inactivation, resulting in faster channel recovery after inactivation. Rapid re-opening of sodium channels most likely underlies the hyperexcitability associated with sodium channel myotonia (Iaizzo et al., 1991; Mitrovi N., et al 1994; Takahashi et al., 2001; Tan et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16624558, 32670189, 25755818, 27415035, 9771789, 1668369, 28877545, 7965854, 21664816, 29050397, 28378410, 18166706, 8242056, 11744749) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 19, 2021 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to impaired SCN4A channel activity (PMID: 7965854). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 30, 2022 | - - |
Paramyotonia congenita of Von Eulenburg Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 10, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1998 | - - |
Hypokalemic periodic paralysis, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11744749; 7965854; 8242056) - PS3_moderate.The c.4765G>A;p.(Val1589Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5905; PMID: 25755818; PMID: 9771789; PMID: 23810313; PMID:23771340; PMID: 18166706; PMID: 16624558) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans; PKD_channel) - PM1. This variant is not present in population databases (rs121908548- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 25755818; 16624558; 9771789) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Hyperkalemic periodic paralysis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 11744749). 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. ClinVar contains an entry for this variant (Variation ID: 5905). This missense change has been observed in individuals with paramyotonia congenita (PMID: 8242056, 9771789, 18166706, 23771340, 23810313, 25755818). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1589 of the SCN4A protein (p.Val1589Met). - |
Potassium-aggravated myotonia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1998 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
N
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at V1589 (P = 0.0261);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at