rs121908544

chr17-63941940-G-Achr17-63941940-G-Cchr17-63941940-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000334.4(SCN4A):c.4342C>T(p.Arg1448Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R1448L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr17-63941939-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-63941940-G-A is Pathogenic according to our data. Variant chr17-63941940-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63941940-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.4342C>T	p.Arg1448Cys	missense_variant	24/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.4342C>T	p.Arg1448Cys	missense_variant	24/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451852 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 720508

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	Reported in the heterozygous state in multiple unrelated families with paramyotonia congenita (Ptacek et al., 1992; Meyer-Kleine et al., 1994); Functional studies indicated that R1448C impacts the channel inactivation in vitro (Chahine et al., 1994; Yang et al., 1994); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 16801039, 8005599, 18166706, 21490317, 26036855, 23417379, 27199537, 12483017, 12552059, 7809121, 30028520, 30930557, 31544778, 32849172, 26484179, 20301669, 32660787, 1316765, 8110459) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2023	This variant has been identified in multiple individuals with paramyotonia congenita and has been shown to associate with paramyotonia congenita in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Cells expressing this variant showed slower current inactivation, faster recovery from inactivation and increased persistent current when compared to WT (PMID: 7809121, 8833340, 21317558). The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SCN4A: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PP4 -

Hyperkalemic periodic paralysis Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1448 of the SCN4A protein (p.Arg1448Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paramyotonia congenita (PMID: 1316765, 8005599, 16801039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5898). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7809121, 8110459, 21490317). This variant disrupts the p.Arg1448 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1316765, 8005599, 8110459). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hypokalemic periodic paralysis, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Apr 01, 2024

A heterozygous missense variant in exon 24 of the SCN4A gene that results in the amino acid substitution of Cysteine for Arginine at codon 1448 (p.Arg1448Cys) was detected. The observed variant has previously been reported in patients in affected with SCN4A related conditions [PMID:16801039]. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant are damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Paramyotonia congenita of Von Eulenburg Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1992

- -

Hypokalemic periodic paralysis, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.4342C>T;p.(Arg1448Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 5898; PMID: 12483017; 12552059; 16801039; 18033047; 21490317; 26484179; 27199537; 26036855; 30028520) - PS4.This variant is not present in population databases (rs121908544, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 5899; 221263; 221262) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 12483017; 16801039; 18033047; 26484179) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.97		Loss of MoRF binding (P = 0.0189);
MVP		0.97
MPC		0.44
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.97
gMVP		0.89

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

Other links and lift over

dbSNP: rs121908544; hg19: chr17-62019300;