rs121908546

Variant names:

• chr17-63951866-G-A
• rs121908546
• NM_000334.4:c.2411C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-63951866-G-A
• chr17-63951866-G-C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000334.4(SCN4A):​c.2411C>T​(p.Ser804Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,040 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. S804C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0
• Publications: 10 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.

• PM1: In a repeat II (size 272) in uniprot entity SCN4A_HUMAN there are 27 pathogenic changes around while only 3 benign (90%) in NM_000334.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.986
• PP5: Variant 17-63951866-G-A is Pathogenic according to our data. Variant chr17-63951866-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5901.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.2411C>T	p.Ser804Phe	missense_variant	Exon 14 of 24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.2411C>T	p.Ser804Phe	missense_variant	Exon 14 of 24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690562

African (AFR) AF: 0.00 AC: 0 AN: 32278

American (AMR) AF: 0.00 AC: 0 AN: 37856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25288

East Asian (EAS) AF: 0.00 AC: 0 AN: 36954

South Asian (SAS) AF: 0.00 AC: 0 AN: 80252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084332

Other (OTH) AF: 0.00 AC: 0 AN: 58364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Mar 23, 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 (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to disrupt skeletal muscle sodium channel inactivation through alterations in voltage dependent gating. (PMID: 9618291, 9660885, 10682917) -

Feb 18, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a family with myotonia and increased creatine kinase (PMID: 7980103); Reported previously as a pathogenic heterozygous variant in a patient with atypical myotonia (PMID: 37273706); Published functional studies demonstrate that p.(S804F) impairs fast inactivation, but does not impact slow inactivation, consistent with other variants associated with potassium myotonia (PMID: 9618291, 9660885, 10682917); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23771340, 11744749, 16392038, 9618291, 10682917, 9660885, 7980103, 37273706, 1338909) -

Paramyotonia congenita/myotonia congenita Pathogenic:1

Nov 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial hyperkalemic periodic paralysis Pathogenic:1

Sep 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 804 of the SCN4A protein (p.Ser804Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant paramyotonia congenita and/or myotonia congenita (PMID: 1338909, 7980103). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5901). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN4A function (PMID: 9618291, 10682917, 11744749, 16392038). For these reasons, this variant has been classified as Pathogenic. -

Myotonia fluctuans Pathogenic:1

Nov 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.14	B
Vest4		0.95
MutPred		0.91		Loss of disorder (P = 0.0061);
MVP		0.95
MPC		0.91
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.91
Mutation Taster		=3/97	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: rs121908546; hg19: chr17-62029226;