Submissions for variant NM_000334.4(SCN4A):c.2623C>T (p.Pro875Ser)

gnomAD frequency: 0.00134  dbSNP: rs201148948

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000279770	SCV000405196	uncertain significance	Congenital myasthenic syndrome 16	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000334804	SCV000405197	benign	Paramyotonia congenita of Von Eulenburg	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001084946	SCV000405198	benign	Familial hyperkalemic periodic paralysis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000299674	SCV000405199	benign	Potassium-aggravated myotonia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000358171	SCV000405200	benign	Hypokalemic periodic paralysis, type 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000489566	SCV000577015	likely benign	not specified	2017-11-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084946	SCV000658537	likely benign	Familial hyperkalemic periodic paralysis	2025-02-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000489566	SCV000677464	benign	not specified	2021-06-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000761997	SCV000892230	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SCN4A: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000489566	SCV005883400	likely benign	not specified	2024-12-16	criteria provided, single submitter	clinical testing	Variant summary: SCN4A c.2623C>T (p.Pro875Ser) results in a non-conservative amino acid change located in the sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 1448708 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN4A causing Congenital Myopathy 22A, Classic phenotype (0.0011). c.2623C>T has been reported in the literature in individuals within a family with atrioventricular nodal re-entry tachycardia (e.g, Andreasen_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Myopathy 22A, Classic. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29396561). ClinVar contains an entry for this variant (Variation ID: 324531). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000761997	SCV001799768	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000761997	SCV001932124	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537818	SCV004740374	likely benign	SCN4A-related disorder	2023-02-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).