chr17-63951866-G-A

Position:

• chr17-63951866-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 ENST00000435607.3(SCN4A):​c.2411C>T​(p.Ser804Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S804C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SCN4A ENST00000435607.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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 repeat II (size 272) in uniprot entity SCN4A_HUMAN there are 54 pathogenic changes around while only 6 benign (90%) in ENST00000435607.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-63951866-G-A is Pathogenic according to our data. Variant chr17-63951866-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63951866-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.2411C>T	p.Ser804Phe	missense_variant	14/24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.2411C>T	p.Ser804Phe	missense_variant	14/24	1	NM_000334.4	ENSP00000396320	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690562

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: 9.22e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 23, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to disrupt skeletal muscle sodium channel inactivation through alterations in voltage dependent gating. (PMID: 9618291, 9660885, 10682917) -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2015	The S804F variant in the SCN4A gene has been reported in a family segregating an autosomal dominant form of myotonia with overlapping features of paramyotonia congenita and myotonia congenita. This variant was found to co-segregate with the phenotype in all family members tested and was not observed in 100 control chromosomes (McClatchey et al., 1992). The S804F variant was not observed in approximately 6,200 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 S804F variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (A799S) has been reported in the Human Gene Mutation Database in association with severe neonatal episodic laryngospasm (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret S804F as a strong candidate for a disease-causing variant; however, the possibility it may be a rare benign variant cannot be excluded -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 18, 2021	- -

Paramyotonia congenita/myotonia congenita Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1994

- -

Familial hyperkalemic periodic paralysis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN4A function (PMID: 9618291, 10682917, 11744749, 16392038). 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: 5901). This missense change has been observed in individual(s) with autosomal dominant paramyotonia congenita and/or myotonia congenita (PMID: 1338909, 7980103). 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 serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 804 of the SCN4A protein (p.Ser804Phe). -

Myotonia fluctuans Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.14	B
Vest4		0.95
MutPred		0.91		Loss of disorder (P = 0.0061);
MVP		0.95
MPC		0.91
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.91

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: rs121908546; hg19: chr17-62029226;