Submissions for variant NM_000334.4(SCN4A):c.4307T>C (p.Leu1436Pro)

dbSNP: rs1598405334

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000819512	SCV000960177	pathogenic	Hyperkalemic periodic paralysis	2021-06-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with autosomal dominant paramyotonia congenita in several families (PMID: 18166706, 23516313, 26036855, 21664816). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1436 of the SCN4A protein (p.Leu1436Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.
Athena Diagnostics Inc	RCV000992899	SCV001145487	pathogenic	not provided	2019-05-08	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/248026 chr). Statistically enriched in uncharacterized patients compared to unmatched population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265548	SCV001443699	pathogenic	SCN4A-Related Disorders	2020-04-04	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in multiple patients with paramyotonia congenita and myotonia, and was observed to segregate with disease in several families (PMID: 18166706, 26036855, 21664816). The p.Leu1436Pro variant has been reported in the ClinVar database (Variation ID: 661981). It is absent from the gnomAD population database and thus is presumed to be rare. The c.4307T>C (p.Leu1436Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.4307T>C (p.Leu1436Pro) variant is classified as Pathogenic.
GeneDx	RCV000992899	SCV002032797	pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing	Not observed at 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: 26659129, 25880512, 33759219, 29088983, 32083589, 23516313, 33325393, 18166706, 29606556, 26036855, 23810313, 23884711, 21698652, 27535533, 21664816)
CeGaT Center for Human Genetics Tuebingen	RCV000992899	SCV004704339	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SCN4A: PP1:Strong, PM1, PM2, PS4:Moderate