NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 16, 2023
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:: RCV001200229.32

Allele description [Variation Report for NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)]

NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)

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.4364T>C (p.Ile1455Thr)

HGVS:

NC_000017.11:g.63941918A>G
NG_011699.1:g.36001T>C
NG_042788.1:g.24826A>G
NM_000334.4:c.4364T>CMANE SELECT
NP_000325.4:p.Ile1455Thr
NC_000017.10:g.62019278A>G

Protein change:

I1455T

Links:

dbSNP: rs377176361

NCBI 1000 Genomes Browser:

rs377176361

Molecular consequence:

NM_000334.4:c.4364T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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UI-R-BJ1-aun-e-07-0-UI.s1 UI-R-BJ1 Rattus norvegicus cDNA clone UI-R-BJ1-aun-e-0...
UI-R-BJ1-aun-e-07-0-UI.s1 UI-R-BJ1 Rattus norvegicus cDNA clone UI-R-BJ1-aun-e-07-0-UI 3', mRNA sequence
gi|8502503|gnl|dbEST|4666729|gb|BE1 .1|

Nucleotide
ae26d10.s1 Soares_NbHFB Homo sapiens cDNA clone IMAGE:896947 3', mRNA sequence
ae26d10.s1 Soares_NbHFB Homo sapiens cDNA clone IMAGE:896947 3', mRNA sequence
gi|2838747|gnl|dbEST|1501091|gb|AA7 .1|

Nucleotide
protein ABHD1 isoform X1 [Homo sapiens]
protein ABHD1 isoform X1 [Homo sapiens]
gi|767915326|ref|XP_011531437.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001371133	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2023)	germline	clinical testing	Citation Link,
SCV001476854	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Sep 6, 2022)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31127727, 28024841, 29606556, 26467025
SCV002019131	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003926173	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 15, 2022)	germline	clinical testing	Citation Link

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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	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service.

Westra D, Schouten MI, Stunnenberg BC, Kusters B, Saris CGJ, Erasmus CE, van Engelen BG, Bulk S, Verschuuren-Bemelmans CC, Gerkes EH, de Geus C, van der Zwaag PA, Chan S, Chung B, Barge-Schaapveld DQCM, Kriek M, Sznajer Y, van Spaendonck-Zwarts K, van der Kooi AJ, Krause A, Schönewolf-Greulich B, de Die-Smulders C, et al.

J Neuromuscul Dis. 2019;6(2):241-258. doi: 10.3233/JND-180376.

PubMed [citation]

PMID:: 31127727

A novel Ile1455Thr variant in the skeletal muscle sodium channel alpha-subunit in a patient with a severe adult-onset proximal myopathy with electrical myotonia and a patient with mild paramyotonia phenotype.

Bednarz M, Stunnenberg BC, Kusters B, Kamsteeg EJ, Saris CG, Groome J, Winston V, Meola G, Jurkat-Rott K, Voermans NC.

Neuromuscul Disord. 2017 Feb;27(2):175-182. doi: 10.1016/j.nmd.2016.09.023. Epub 2016 Oct 19.

PubMed [citation]

PMID:: 28024841

See all PubMed Citations (5)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001371133.24

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

SCN4A: PM1, PM2, PP1:Moderate, PS4:Moderate, PP3, PP4, PS3:Supporting

#	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		2	not provided	not provided	not provided

From Athena Diagnostics, SCV001476854.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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 myotonia. Additionally, in our internal patient population, this variant is statistically more frequent than in the general population. Assessment of experimental evidence suggests this variant results in abnormal protein function. Functional studies suggest complex effects on SCN4A caused by the variant, including slower current inactivation and decrease in overall current levels (PMID:28024841). The variant is located in a region that is considered important for protein function and/or structure.

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

From Revvity Omics, Revvity, SCV002019131.3

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

#	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, SCV003926173.1

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

Description

Published functional studies demonstrate destabilization in the inactivated state which is a typical pathogenic mechanism for sodium channel myotonia and paramyotonia congenita (Bednarz et al., 2017); 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: 29606556, 31127727, 28024841, 30420713)

#	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

Last Updated: Oct 20, 2024

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