chr17-63941930-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000334.4(SCN4A):c.4352G>A(p.Arg1451His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456250Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 723404
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hyperkalemic periodic paralysis Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1451 of the SCN4A protein (p.Arg1451His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant SCN4A-related conditions (PMID: 27922499, 35907044; internal data). ClinVar contains an entry for this variant (Variation ID: 448280). 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 80%. This variant disrupts the p.Arg1451 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29391559, 29946067). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function (LoF) and gain of function (GoF) are known mechanisms of disease in this gene and are associated with SCN4A-related disease. GoF is a well characterised disease mechanism for autosomal dominant SCN4A-related diseases, while LoF is a mechanism associated with autosomal recessive SCN4A-related diseases (PMID: 26700687, OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Phenotypes involving paralysis and myotonia are typically inherited in a dominant manner, whereas myasthenic syndrome and congenital myopathy display recessive inheritance (OMIM, PMID: 26700687). (I) 0115 - Variants in this gene are known to have variable expressivity. Some individuals carrying pathogenic variants do not present with a typical clinical phenotype, however they do have detectable signs of myotonia on EMG (PMID: 20301669). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ion transport protein domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative changes have been observed in at least five individuals in the literature with SCN4A-related conditions. This includes several affected heterozygotes, and one homozygote who was affected with hypokalemic periodic paralysis (PMIDs: 29946067, 29391559). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by two clinical laboratories in ClinVar, and was observed in an individual with hyperkalemia and gait abnormalitites who was homozygous for this variant. This variant has also been observed as heterozygous in one individual in the literature who had a genetically confirmed diagnosis of myotonic dystrophy 2, in whom the SCN4A variant was thought to explain their severe muscle pain (PMID: 27922499). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 09, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 02, 2021 | - - |
SCN4A-related non-dystrophic myotonia Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences | Apr 06, 2022 | - - |
Hypokalemic periodic paralysis, type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences | Apr 12, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at