rs1555601448

Positions:

• chr17-63945607-G-A

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.3473C>T​(p.Pro1158Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1158S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 18 ACMG points.

• PM1: In a helix (size 25) in uniprot entity SCN4A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr17-63945608-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 17-63945607-G-A is Pathogenic according to our data. Variant chr17-63945607-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.3473C>T	p.Pro1158Leu	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.3473C>T	p.Pro1158Leu	missense_variant	19/24	1	NM_000334.4	ENSP00000396320	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 20, 2017

- -

Familial hyperkalemic periodic paralysis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2022

Experimental studies have shown that this missense change affects SCN4A function (PMID: 27164696). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1158 of the SCN4A protein (p.Pro1158Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myotonia permanens (PMID: 27164696). ClinVar contains an entry for this variant (Variation ID: 448275). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro1158 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10851391, 21221019). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-9.5	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.071	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.75		Gain of MoRF binding (P = 0.3555);
MVP		0.98
MPC		0.92
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.94

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: rs1555601448; hg19: chr17-62022967; COSMIC: COSV105354284; COSMIC: COSV105354284;