17-63945614-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000334.4(SCN4A):c.3466G>A(p.Ala1156Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,613,762 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. A1156S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.08

Variant links:

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]

SCN4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 16) in uniprot entity SCN4A_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000334.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-63945614-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

PP5

Variant 17-63945614-C-T is Pathogenic according to our data. Variant chr17-63945614-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63945614-C-T is described in Lovd as [Pathogenic]. Variant chr17-63945614-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4 link	c.3466G>A	p.Ala1156Thr	missense_variant	Exon 19 of 24	ENST00000435607.3	NP_000325.4	P35499

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.3466G>A	p.Ala1156Thr	missense_variant	Exon 19 of 24	1	NM_000334.4	ENSP00000396320.1		P35499

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000559

AC:

AN:

250384

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000656

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000360

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 23, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant results in altered channel inactivation and voltage dependence compared to wild-type controls (Yang et al., 1994; Hayward et al., 1999; Palmio et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 7809121, 22016737, 10227633, 14501839, 22926674, 20076800, 16193245, 1338909, 28330959, 31440732, 32849172, 32619119) -

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2019

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The best available variant frequency is 3-10 times higher than the disease allele frequency, and data include at least 10 observations. Statistically enriched in uncharacterized patients compared to unmatched population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. -

Hyperkalemic periodic paralysis

Pathogenic:2

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1156 of the SCN4A protein (p.Ala1156Thr). This variant is present in population databases (rs80338958, gnomAD 0.05%). This missense change has been observed in individuals with autosomal dominant SCN4A-related disease (PMID: 1338909, 28330959). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5900). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7809121, 28330959). For these reasons, this variant has been classified as Pathogenic. -

Jan 11, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Mar 08, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3466G>A (p.A1156T) alteration is located in exon 19 (coding exon 19) of the SCN4A gene. This alteration results from a G to A substitution at nucleotide position 3466, causing the alanine (A) at amino acid position 1156 to be replaced by a threonine (T). _x000D_ _x000D_ The SCN4A c.3466G>A (p.A1156T) alteration is classified as pathogenic for autosomal dominant SCN4A-related myotonia and/or periodic paralysis disorders; however, its clinical significance for autosomal recessive SCN4A-related congenital myasthenic syndrome is unclear. Based on data from gnomAD, the A allele has an overall frequency of 0.005% (15/281704) total alleles studied. The highest observed frequency was 0.044% (11/25072) of European (Finnish) alleles. This alteration has been reported in multiple individuals and families with clinical features consistent with SCN4A-related myotonia and/or periodic paralysis disorders (McClatchey, 1992; Lee, 2009; Song, 2012; Palmio, 2017; Sainio, 2022). EMG myotonic discharges have been detected in multiple individuals with this variant (Palmio, 2017). Another alteration at the same codon, c.3466G>T (p.A1156S), has been described in an individual with sodium-channel myotonia (Maggi, 2020). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.A1156T alteration exhibited a disturbance in channel inactivation compared to the wild-type (Yang, 1994; Palmio, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Paramyotonia congenita/hyperkalemic periodic paralysis

Pathogenic:1

Oct 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Focal-onset seizure

Pathogenic:1

Mar 31, 2022

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SCN4A-related disorder

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in patients with paramyotonia congenita, hyperkalaemic periodic paralysis, exercise- and cold-induced muscle cramps, muscle stiffness, myalgia, and generalized seizures (PMID: 1338909, 28330959, 22926674, 31440732, 34418069). Different amino acid changes at the same residue (p.Ala1156Ser) have been previously reported in individuals with myotonia and periodic paralyses (PMID: 32849172). Functional studies showed that the c.3466G>A (p.Ala1156Thr) variant resulted in mild attenuation and disturbance of channel inactivation due to reduced macroscopic rate, accelerated recovery, and altered voltage dependence (PMID: 1338909, 7809121, 28330959). The c.3466G>A (p.Ala1156Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/281704) and thus is presumed to be rare. The c.3466G>A (p.Ala1156Thr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3466G>A (p.Ala1156Thr) variant is classified as Pathogenic. -

Potassium-aggravated myotonia

Pathogenic:1

Mar 30, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was previously reported in a family of Finnish origin with incomplete penetrance and the members were reported with variable phenotypes, but it was found to be consistent with the features of HYPP, PMC, and myotonia [PMID: 1338909]. In addition, this variant was reported in multiple myalgia patients with clinical features of exercise- and cold-induced muscle cramps, muscle stiffness [PMID: 28330959] and also in two Korean patients exhibiting the myotonia and HYPP phenotypes, respectively [ PMID: 20076800]. Functional studies using invitro transfection assays showed fast inactivation in cells harboring variant p.A1156T channel was mildly attenuated in comparison to cells with wild-type channel suggesting the gain of function [PMID: 28330959] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Benign

0.078

Polyphen

1.0

Vest4

0.87

MVP

0.95

MPC

0.89

ClinPred

0.81

GERP RS

3.9

Varity_R

0.87

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over