NM_001365536.1(SCN9A):c.3004G>T (p.Val1002Leu) AND Primary erythromelalgia

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 27, 2017
Review status:: criteria provided, conflicting classifications

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:: RCV000490436.17

Allele description [Variation Report for NM_001365536.1(SCN9A):c.3004G>T (p.Val1002Leu)]

NM_001365536.1(SCN9A):c.3004G>T (p.Val1002Leu)

Genes:

SCN1A-AS1:SCN1A and SCN9A antisense RNA 1 [Gene - HGNC]
SCN9A:sodium voltage-gated channel alpha subunit 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q24.3

Genomic location:

Preferred name:

NM_001365536.1(SCN9A):c.3004G>T (p.Val1002Leu)

Other names:

V991L

HGVS:

NC_000002.12:g.166272746C>A
NG_012798.1:g.108242G>T
NM_001365536.1:c.3004G>TMANE SELECT
NM_002977.4:c.2971G>T
NP_001352465.1:p.Val1002Leu
NP_002968.1:p.Val991Leu
NP_002968.1:p.Val991Leu
NP_002968.2:p.Val991Leu
LRG_369t1:c.2971G>T
LRG_369:g.108242G>T
LRG_369p1:p.Val991Leu
NC_000002.11:g.167129256C>A
NM_002977.2:c.2971G>T
NM_002977.3:c.2971G>T

Protein change:

V1002L; VAL991LEU

Links:

OMIM: 603415.0025; dbSNP: rs4369876

NCBI 1000 Genomes Browser:

rs4369876

Molecular consequence:

NM_001365536.1:c.3004G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002977.4:c.2971G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Primary erythromelalgia
Synonyms:: Erythermalgia, primary; SCN9A-Related Inherited Erythromelalgia
Identifiers:: MONDO: MONDO:0007571; MedGen: C0014805; Orphanet: 306577; Orphanet: 90026; OMIM: 133020

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267491	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 21698661, 25741868
SCV000418510	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV001435123	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267491

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 18, 2016)

germline

reference population

PubMed (2)
[See all records that cite these PMIDs]

SCV000418510

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Benign
(Apr 27, 2017)

germline

clinical testing

Citation Link,

SCV001435123

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign

germline

research

PubMed (1)
[See all records that cite this PMID]

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	not provided	not provided	not provided	not provided	not provided	research
East Asian	germline	unknown	4	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy.

Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS.

Ann Neurol. 2012 Jan;71(1):26-39. doi: 10.1002/ana.22485. Epub 2011 Jun 22.

PubMed [citation]

PMID:: 21698661

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267491.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	4	not provided	not provided	reference population	PubMed (2)

#	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		4	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000418510.3

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001435123.1

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

Description

The heterozygous p.Val991Leu variant in SCN9A has been identified in an individual suspected to have small fibre neuropathy (PMID: 21698661). In vitro functional studies provide some evidence that the p.Pro124Ser variant will not impact protein function (PMID: 21698661). However, these types of assays may not accurately represent biological function. This variant is classified as benign for autosomal dominant small fibre neuropathy because it has been identified in >20% of Latino chromosomes, including 340 homozygotes, by ExAC (http://gnomad.broadinstitute.org/).

#	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: Apr 20, 2024

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