rs121908549

Positions:

• chr17-63945602-T-C

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.3478A>G​(p.Ile1160Val) 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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.95

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, 0.982
• PP5: Variant 17-63945602-T-C is Pathogenic according to our data. Variant chr17-63945602-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63945602-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.3478A>G	p.Ile1160Val	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.3478A>G	p.Ile1160Val	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2017	The I1160V variant in the SCN4A gene has been reported previously in the heterozygous state in mutiple unrelatedindividuals with acetazolamide-responsive myotonia congenita or paramyotonia congenita(Jurkatt-Rott et al., 2004; Al-Ghamdi et al., 2017). Functional studies demonstrate that the I1160Vvariant has faster rates of closed-state fast inactivation onset and recovery as well as slowerdeactivation as compared to wild-type (Richmond et al., 1997). The I1160V variant is not observed inlarge population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). The I1160V variant is a conservative amino acid substitution that occurs at a position that isconserved across species. We interpret I1160V as a pathogenic variant. -

Myotonia congenita, atypical, acetazolamide-responsive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1994

- -

Hyperkalemic periodic paralysis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 05, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1160 of the SCN4A protein (p.Ile1160Val). This missense change has been observed in individuals with clinical features of myotonia congenita (PMID: 8058156, 22759684, 29606556; Invitae). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 9336185). 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: 5906). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.98	N
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.017	D
Polyphen		0.83	P
Vest4		0.91
MutPred		0.90		Gain of catalytic residue at I1160 (P = 0.0207);
MVP		0.93
MPC		0.68
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.89
gMVP		0.63

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: rs121908549; hg19: chr17-62022962;