Submissions for variant NM_000334.4(SCN4A):c.2024G>A (p.Arg675Gln)

gnomAD frequency: 0.00001  dbSNP: rs121908557

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516541	SCV000615067	pathogenic	not provided	2023-11-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features of hyperkalemic, hypokalemic and normokalemic periodic paralysis and has been shown to associate with disease in multiple families. 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. (PMID: 19052238) The variant is located in a region that is considered important for protein function and/or structure.
Undiagnosed Diseases Network, NIH	RCV000543491	SCV000622166	pathogenic	Myopathy	2016-08-12	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found twice in our study in trans with a nonsense variant (R1142X) in a set of siblings with severe congenital hypotonia, which resolved after infancy, and congenital heart defects.
Baylor Genetics	RCV000206996	SCV000807201	pathogenic	Hyperkalemic periodic paralysis	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found three times in our laboratory: paternally inherited (from a healthy father) in a 7-month-old female with profound neonatal hypotonia & early delays, sister with similar presentation with resolution of symptoms in later childhood [variant was in trans with a nonsense variant, and both sibs compound heterozygous]; maternally inherited in a 13-year-old female with hypertonia, spasticity, gait abnormality, headaches; in a 1-year-old male with hearing loss and cryptorchidism, and a de novo pathogenic PTPN11 variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206996	SCV000949437	pathogenic	Hyperkalemic periodic paralysis	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 675 of the SCN4A protein (p.Arg675Gln). This variant is present in population databases (rs121908557, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant hyperkalemic periodic paralysis, hypokalemic periodic paralysis and normokalemic periodic paralysis (PMID: 15596759, 18046642, 19065518, 19225109, 22926674, 25839108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5919). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 19052238, 19065518, 24682880). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg675 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15596759, 22926674, 23516313). 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.
Baylor Genetics	RCV003147276	SCV003835568	pathogenic	Congenital myasthenic syndrome 16	2022-09-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV003335018	SCV004045844	pathogenic	Hypokalemic periodic paralysis, type 2	2023-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000516541	SCV005389147	pathogenic	not provided	2024-05-02	criteria provided, single submitter	clinical testing	Observed in multiple unrelated individuals with hyperkalemic periodic paralysis, hypokalemic periodic paralysis and normokalemic periodic paralysis in published literature (PMID: 31567646, 33345742, 38609989, 15596759, 22926674); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); 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: 19065518, 25839108, 20301669, 33263785, 19225109, 19052238, 31708864, 31068157, 34992632, 33965302, 18046642, 19201608, 24682880, 33345742, 15596759, 22926674, 38609989, 31567646)
Fulgent Genetics, Fulgent Genetics	RCV005025013	SCV005651800	pathogenic	Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16; Congenital myopathy 22A, classic; Congenital myopathy 22B, severe fetal	2024-03-07	criteria provided, single submitter	clinical testing
OMIM	RCV000006282	SCV000026464	pathogenic	Normokalemic periodic paralysis, potassium-sensitive	2004-12-14	no assertion criteria provided	literature only
GeneReviews	RCV000206996	SCV000262569	not provided	Hyperkalemic periodic paralysis		no assertion provided	literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000206996	SCV002754554	pathogenic	Hyperkalemic periodic paralysis	2022-10-18	no assertion criteria provided	clinical testing