rs80338962

Variant names:

• chr17-63941508-T-C
• rs80338962
• NM_000334.4:c.4774A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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: Genomes: not found (cov: 32)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 8.02
• Publications: 57 publications found

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 Gene-Disease associations (from GenCC):

• hyperkalemic periodic paralysis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• paramyotonia congenita of Von Eulenburg

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• SCN4A-related myopathy, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• hypokalemic periodic paralysis, type 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• potassium-aggravated myotonia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 16

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital myopathy 22A, classic

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• acetazolamide-responsive myotonia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myotonia fluctuans

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myotonia permanens

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000334.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-63941506-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 427072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 97 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 1.5606 (below the threshold of 3.09). Trascript score misZ: 2.2224 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 16, paramyotonia congenita of Von Eulenburg, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, type 2, congenital myopathy, hypokalemic periodic paralysis, SCN4A-related myopathy, autosomal recessive, congenital myopathy 22A, classic, potassium-aggravated myotonia, postsynaptic congenital myasthenic syndrome, myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-63941508-T-C is Pathogenic according to our data. Variant chr17-63941508-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.4774A>G	p.Met1592Val	missense_variant	Exon 24 of 24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.4774A>G	p.Met1592Val	missense_variant	Exon 24 of 24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Aug 21, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_Moderate, PM2, PP1, PP3 -

Feb 02, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN4A: PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3 -

Dec 21, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Familial hyperkalemic periodic paralysis Pathogenic:3 Other:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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) 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. -

Mar 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 12, 2022

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Paramyotonia congenita of Von Eulenburg;C0238357:Familial hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C5830453:Congenital myopathy 22A, classic;C5830501:Congenital myopathy 22B, severe fetal Pathogenic:1

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy 22A, classic Pathogenic:1

May 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN4A c.4774A>G (p.Met1592Val) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 250100 control chromosomes (gnomAD). c.4774A>G has been observed in multiple individuals affected with clinical features of SCN4A-Related Disorder (Feero_1993, Miller_2004). These data indicate that the variant is very likely to be associated with disease. At least two publications reported experimental evidence evaluating an impact on protein function and this variant affected the SCN4A protein function (Feng_2009, Lucas_2014). The following publications have been ascertained in the context of this evaluation (PMID: 8385748, 19290024, 24714718, 15534250). ClinVar contains an entry for this variant (Variation ID: 5897). Based on the evidence outlined above, the variant was classified as pathogenic. -

Paramyotonia congenita/hyperkalemic periodic paralysis Pathogenic:1

Mar 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Paramyotonia congenita of Von Eulenburg;C0238357:Familial 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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.96
MutPred		0.90		Gain of catalytic residue at M1592 (P = 0.0708);
MVP		0.95
MPC		0.91
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.91
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80338962; hg19: chr17-62018868;