Submissions for variant NM_000334.4(SCN4A):c.2919del (p.Glu974fs)

dbSNP: rs1567819905

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799405	SCV000939065	pathogenic	Familial hyperkalemic periodic paralysis	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu974Argfs*67) in the SCN4A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN4A are known to be pathogenic (PMID: 26700687). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 645345). For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458169	SCV004177149	likely pathogenic	Congenital myopathy	2023-08-02	criteria provided, single submitter	clinical testing	The paternally inherited SCN4A c.2919del (p.Glu974fs) variant, to our knowledge, has not been reported in the medical literature. This variant causes a frameshift by deleting one nucleotide, leading to a premature termination codon and nonsense mediated decay; loss of SCN4A function is a known mechanism of disease. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been submitted to the ClinVar database as pathogenic by one clinical laboratory (Variation ID: 645345). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.