17-63971201-G-A

Variant names:

• chr17-63971201-G-A
• rs527236148
• NM_000334.4:c.664C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000334.4(SCN4A):​c.664C>T​(p.Arg222Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,414,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R222G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.99
• Publications: 25 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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-63971200-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1331173.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, 0.981
• PP5: Variant 17-63971201-G-A is Pathogenic according to our data. Variant chr17-63971201-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143199.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.664C>T	p.Arg222Trp	missense_variant	Exon 5 of 24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.664C>T	p.Arg222Trp	missense_variant	Exon 5 of 24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000554 AC: 1 AN: 180446 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1414838 Hom.: 0 Cov.: 33 AF XY: 0.00000286 AC XY: 2 AN XY: 699270

African (AFR) AF: 0.00 AC: 0 AN: 32472

American (AMR) AF: 0.0000263 AC: 1 AN: 38050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 37248

South Asian (SAS) AF: 0.00 AC: 0 AN: 80290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1086962

Other (OTH) AF: 0.0000171 AC: 1 AN: 58598

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperkalemic periodic paralysis Pathogenic:2

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 222 of the SCN4A protein (p.Arg222Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypokalemic periodic paralysis (PMID: 19118277, 21189962, 21841462, 29419865). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143199). 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 80%. For these reasons, this variant has been classified as Pathogenic.

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

not provided Pathogenic:2

Apr 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with hypokalemic periodic paralysis in published literature and referred for genetic testing at GeneDx (PMID: 19118277, 29991727); Published functional studies demonstrate that this variant results in decreased sodium current and slowed channel activation (PMID: 29991727); 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: 29419865, 21841462, 29991727, 29636418, 21189962, 31772215, 32407401, 19118277)

Jun 24, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_Moderate, PM2, PP3, PP1

SCN4A-related disorder Pathogenic:2

Nov 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN4A c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant has been reported in multiple patients with autosomal dominant hypokalemic periodic paralysis (Matthews et al. 2009. PubMed ID: 19118277; Park and Kim. 2010. PubMed ID: 21189962; Sung et al. 2012. PubMed ID: 21841462). This variant is reported in 0.0037% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.

Jan 11, 2024

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

The c.664C>T (p.Arg222Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in patients with hypokalemic periodic paralysis and shown to partially segregate with the disease in families (PMID: 19118277, 29636418, 31772215, 32407401, 36779057, 20301512, 21189962). Functional studies indicate this variant leads to reduced sodium current and slowed channel activation (PMID: 29636418, 31772215, 29991727). The c.664C>T (p.Arg222Trp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (1/180446) and thus is presumed to be rare. Based on the available evidence, c.664C>T (p.Arg222Trp) is classified as Pathogenic.

Hypokalemic periodic paralysis, type 2 Pathogenic:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May 19, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 5 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar, and reported in the literature in heterozygous individuals with hypokalaemic periodic paralysis (PMIDs: 19118277, 29991727, 32407401); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from arginine to tryptophan; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Phenotypes involving paralysis and myotonia are typically inherited in a dominant manner, whereas myasthenic syndrome and congenital myopathy display recessive inheritance (OMIM); Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 2 heterozygote(s), 0 homozygote(s)); Variant is located in the annotated ion transport protein domain (DECIPHER, NCBI); Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN4A-related disease (OMIM). Functional studies of missense variants have demonstrated both loss of function and gain of protein function effects (OMIM); Variants in this gene are known to have variable expressivity. Clinical phenotypes of autosomal recessive congenital myopathy range from severe lethal fetal hypokinesia to a classical form of congenital myopathy that improves with age (PMID: 26700687). In relation to autosomal dominant hyperkalaemic paralysis and myotonia, some individuals carrying pathogenic variants do not present with a typical clinical phenotype; however, they do have detectable signs of myotonia on EMG (PMID: 20301669); Inheritance information for this variant is not currently available in this individual.

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

Sep 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		2.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.95
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.83
gMVP		0.98
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs527236148; hg19: chr17-62048561; COSMIC: COSV71129326; COSMIC: COSV71129326;