rs80338792

chr17-63943846-C-Achr17-63943846-C-Gchr17-63943846-C-T

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.3917G>T(p.Gly1306Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,642 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1306A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.90

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, 7 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 chr17-63943846-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 17-63943846-C-A is Pathogenic according to our data. Variant chr17-63943846-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63943846-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.3917G>T	p.Gly1306Val	missense_variant	22/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.3917G>T	p.Gly1306Val	missense_variant	22/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249512 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135334

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449642 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 721982

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paramyotonia congenita of Von Eulenburg Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005903). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 27415035). Different missense changes at the same codon (p.Gly1306Ala, p.Gly1306Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005908, VCV000005920). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 25, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	Reported previously as a heterozygous variant in two unrelated families with paramyotonia congenita (McClatchey et al., 1992); Functional studies suggest that G1306V results in slower inactivation of the SCN4A sodium channel (Lerche et al., 1993); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 8308722, 1310898, 27415035, 26944947, 18337100, 18337730, 28150151, 26885337, 26080010, 22094069, 20445432, 17823953, 16832098, 8044656, 16392038, 7473241, 32849172, 32660787) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with paramyotonia congenita in multiple families, and is reported in multiple other unrelated individuals with non-dystrophic myotonia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies indicate that this variant disrupts normal ion channel properties, resulting in aberrant channel regulation of current and signaling (PMID: 7473241, 16392038). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SCN4A: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting -

Hyperkalemic periodic paralysis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 11, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1306 of the SCN4A protein (p.Gly1306Val). This variant is present in population databases (rs80338792, gnomAD 0.0009%). This missense change has been observed in individuals with paramyotonia congenita (PMID: 1310898, 8044656, 8308722, 17823953, 18337100, 18337730, 20445432, 22094069, 27415035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5903). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7473241, 16392038). This variant disrupts the p.Gly1306 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7980103, 16832098, 20713951, 25088311, 25311598, 26080010, 26885337, 26944947). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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

- -

Potassium-aggravated myotonia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.80	P
Vest4		0.75
MutPred		0.81		Loss of disorder (P = 0.0258);
MVP		0.88
MPC		0.52
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.81
gMVP		0.64

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: rs80338792; hg19: chr17-62021206;