rs121908555

Positions:

• chr17-63945608-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000334.4(SCN4A):​c.3472C>T​(p.Pro1158Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.92

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 17-63945608-G-A is Pathogenic according to our data. Variant chr17-63945608-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63945608-G-A is described in Lovd as [Pathogenic]. Variant chr17-63945608-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-63945608-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.3472C>T	p.Pro1158Ser	missense_variant	19/24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.3472C>T	p.Pro1158Ser	missense_variant	19/24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2024	Observed in affected individuals with myotonia in several unrelated families in published literature. Additional individuals within these same families also share a similar phenotype suggesting autosomal dominant inheritance, however segregation data could not be confirmed (PMID: 10851391, 29606556); Published functional studies demonstrate a damaging effect resulting in SCN4A, the alpha subunit of the sodium channel, having greater sensitivity to pH and temperature changes (PMID: 29674667, 14557559); 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: 25454733, 17898326, 16193245, 16195244, 14557559, 33836525, 34027742, Ghovanloo2021, 21221019, 26986070, 33325393, 32527974, 28940424, 18337730, 10851391, 29606556, 29674667) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2016	- -

Hypokalemic periodic paralysis, type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 14, 2003

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

The c.3472C>T (p.P1158S) alteration is located in exon 19 (coding exon 19) of the SCN4A gene. This alteration results from a C to T substitution at nucleotide position 3472, causing the proline (P) at amino acid position 1158 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to segregate with disease in multiple families with myotonia and periodic paralysis (Sugiura, 2000; Modoni, 2011). In addition, alterations affecting the same amino acid, p.P1158L and p.P1158A, have been reported in patients with myotonia (Desaphy 2016; Xu, 2018). Patch clamp experiments showed temperature-dependent negative shifts in the voltage dependence of activation and inactivation as well as a slower rate of inactivation for the P1158S channels as compared to wild type channels (Sugiura, 2003). Voltage-clamp studies of Na currents showed that wildtype and P1158S channels displayed comparable behavior at 37 °C, but upon cooling to 25 °C, mutant channels activated at more negative potentials and slow inactivation was destabilized (Webb, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Hyperkalemic periodic paralysis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2022

This missense change has been observed in individuals with myotonia congenita (PMID: 10851391, 21221019). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1158 of the SCN4A protein (p.Pro1158Ser). ClinVar contains an entry for this variant (Variation ID: 5917). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 14557559, 17898326). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.84		Gain of MoRF binding (P = 0.2968);
MVP		0.96
MPC		0.91
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121908555; hg19: chr17-62022968;