17-63943846-C-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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 Pathogenic.
Frequency
Consequence
NM_000334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249512Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135334
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1449642Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 721982
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Paramyotonia congenita of Von Eulenburg Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 20, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | 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:4
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 13, 2024 | PP3, PM1, PM2, PM5, PS4 - |
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 - |
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) - |
Hyperkalemic periodic paralysis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 17, 2024 | 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN4A protein function with a positive predictive value of 95%. 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. - |
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. - |
Potassium-aggravated myotonia Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PS4+PM5_Strong+PP3_Moderate - |
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 | - - |
Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C5830453:Congenital myopathy 22A, classic;C5830501:Congenital myopathy 22B, severe fetal Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at