NM_000334.4(SCN4A):c.3917G>T (p.Gly1306Val) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 1, 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:: RCV000479620.35

Allele description [Variation Report for NM_000334.4(SCN4A):c.3917G>T (p.Gly1306Val)]

NM_000334.4(SCN4A):c.3917G>T (p.Gly1306Val)

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.3917G>T (p.Gly1306Val)

HGVS:

NC_000017.11:g.63943846C>A
NG_011699.1:g.34073G>T
NG_042788.1:g.26754C>A
NM_000334.4:c.3917G>TMANE SELECT
NP_000325.4:p.Gly1306Val
NC_000017.10:g.62021206C>A
P35499:p.Gly1306Val

Protein change:

G1306V; GLY1306VAL

Links:

UniProtKB: P35499#VAR_001569; OMIM: 603967.0007; dbSNP: rs80338792

NCBI 1000 Genomes Browser:

rs80338792

Molecular consequence:

NM_000334.4:c.3917G>T - 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
SCV000567468	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 13, 2021)	germline	clinical testing	Citation Link,
SCV000615092	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 3, 2023)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 28150151, 27415035, 8044656, 7473241, 1310898, 8308722, 32849172, 20445432, 18337730, 33263785, 16786525, 32660787, 16392038, 26467025
SCV001249362	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000567468

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 13, 2021)

germline

clinical testing

Citation Link,

SCV000615092

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(May 3, 2023)

unknown

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV001249362

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

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

Pathogenic
(Jul 1, 2023)

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	yes	5	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

Nothing to display

See all PubMed Citations (14)

Details of each submission

From GeneDx, SCV000567468.4

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

Description

Reported previously as a heterozygous variant in two unrelated families with paramyotonia congenita (McClatchey et al., 1992); Functional studies suggest that G1306V results in slower inactivation of the SCN4A sodium channel (Lerche et al., 1993); Not observed at a 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: 25525159, 8308722, 1310898, 27415035, 26944947, 18337100, 18337730, 28150151, 26885337, 26080010, 22094069, 20445432, 17823953, 16832098, 8044656, 16392038, 7473241, 32849172, 32660787)

#	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 Athena Diagnostics, SCV000615092.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with paramyotonia congenita in multiple families, and is reported in multiple other unrelated individuals with non-dystrophic myotonia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies indicate that this variant disrupts normal ion channel properties, resulting in aberrant channel regulation of current and signaling (PMID: 7473241, 16392038).

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001249362.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

Description

SCN4A: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, 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		5	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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