NM_000334.4(SCN4A):c.4307T>C (p.Leu1436Pro) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000992899.14

Allele description [Variation Report for NM_000334.4(SCN4A):c.4307T>C (p.Leu1436Pro)]

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

Genes:

GH-LCR:growth hormone locus control region [Gene]
SCN4A:sodium voltage-gated channel alpha subunit 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q23.3

Genomic location:

Preferred name:

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

HGVS:

NC_000017.11:g.63941975A>G
NG_011699.1:g.35944T>C
NG_042788.1:g.24883A>G
NM_000334.4:c.4307T>CMANE SELECT
NP_000325.4:p.Leu1436Pro
NC_000017.10:g.62019335A>G

Protein change:

L1436P

Links:

dbSNP: rs1598405334

NCBI 1000 Genomes Browser:

rs1598405334

Molecular consequence:

NM_000334.4:c.4307T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001145487	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 8, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21664816, 26036855, 21698652, 23884711, 18166706, 23810313, 26467025
SCV002032797	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 8, 2021)	germline	clinical testing	Citation Link,
SCV004704339	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001145487

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(May 8, 2019)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002032797

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 8, 2021)

germline

clinical testing

Citation Link,

SCV004704339

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Jan 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Late onset painful cold-aggravated myotonia: three families with SCN4A L1436P mutation.

Bissay V, Keymolen K, Lissens W, Laureys G, Schmedding E, De Keyser J.

Neuromuscul Disord. 2011 Aug;21(8):590-3. doi: 10.1016/j.nmd.2011.05.006. Epub 2011 Jun 12.

PubMed [citation]

PMID:: 21664816

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.

Bissay V, Van Malderen SC, Keymolen K, Lissens W, Peeters U, Daneels D, Jansen AC, Pappaert G, Brugada P, De Keyser J, Van Dooren S.

Eur J Hum Genet. 2016 Mar;24(3):400-7. doi: 10.1038/ejhg.2015.125. Epub 2015 Jun 3.

PubMed [citation]

PMID:: 26036855
PMCID:: PMC4755372

See all PubMed Citations (7)

Details of each submission

From Athena Diagnostics, SCV001145487.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002032797.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004704339.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

SCN4A: PP1:Strong, PM1, PM2, PS4:Moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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