rs80338956

Positions:

• chr17-63957460-A-G

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.2078T>C​(p.Ile693Thr) 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. I693S) 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:5
• Conservation: PhyloP100: 9.32

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr17-63957460-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1918174.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-63957460-A-G is Pathogenic according to our data. Variant chr17-63957460-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63957460-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.2078T>C	p.Ile693Thr	missense_variant	13/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.2078T>C	p.Ile693Thr	missense_variant	13/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	Athena Diagnostics	Jan 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2017	The I693T substitution in the SCN4A gene has been reported multiple times in association with SCN4A-relateddisorders including paramyotonia congenita and hyperkalemic periodic paralysis (Song et al., 2012; Pagon etal., 1993; Matthews et al., 2008; SCN4A LOVD). The I693T variant was not observed in approximately6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The I693T variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution alters a conserved position that is predicted tobe within the cytoplasmic loop between transmembrane segments 4 and 5 in the second homologous repeatdomain. Additionally, missense variants in the same (I693L/M) and nearby (L689I/V) residues have beenreported in the Human Gene Mutation Database in association with SCN4A-related disorders (Stenson et al.,2014). Therefore, we interpret I693T as a pathogenic variant. -

Paramyotonia congenita of Von Eulenburg Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 18, 2008

- -

SCN4A-related non-dystrophic myotonia Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Apr 06, 2022

- -

Hyperkalemic periodic paralysis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 9508833). 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. ClinVar contains an entry for this variant (Variation ID: 5923). This missense change has been observed in individuals with hyperkalemic periodic paralysis and/or paramyotonia congenita (PMID: 2649440, 8902732, 19015492, 20076800, 22926674). 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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 693 of the SCN4A protein (p.Ile693Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.96		Loss of stability (P = 0.0229);
MVP		0.97
MPC		1.0
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.86
gMVP		0.86

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: rs80338956; hg19: chr17-62034820;