VCV000157597.59 - ClinVar

NM_001365536.1(SCN9A):c.2248A>G (p.Ile750Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(16)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(2); Likely benign(11)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001365536.1(SCN9A):c.2248A>G (p.Ile750Val)

Variation ID: 157597 Accession: VCV000157597.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 166280452 (GRCh38) [ NCBI UCSC ] 2: 167136962 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 15, 2014	Oct 20, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001365536.1:c.2248A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001352465.1:p.Ile750Val	missense
NM_002977.4:c.2215A>G	NP_002968.2:p.Ile739Val	missense
NC_000002.12:g.166280452T>C
NC_000002.11:g.167136962T>C
NG_012798.1:g.100536A>G
LRG_369:g.100536A>G
LRG_369t1:c.2215A>G	LRG_369p1:p.Ile739Val

... more HGVS ... less HGVS

Protein change

I750V

Other names

I739V

Canonical SPDI

NC_000002.12:166280451:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00100 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00109

Trans-Omics for Precision Medicine (TOPMed) 0.00237

The Genome Aggregation Database (gnomAD), exomes 0.00245

The Genome Aggregation Database (gnomAD) 0.00278

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00304

Exome Aggregation Consortium (ExAC) 0.00390

Links

ClinGen: CA171007 OMIM: 603415.0027 dbSNP: rs182650126 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN1A-AS1	-	-	-	GRCh38	-	2183
SCN9A		-	-	GRCh38 GRCh37	449	2672

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Small fiber neuropathy	Pathogenic (1)	no assertion criteria provided	Sep 1, 2014	RCV000144932.14
Neuropathy, hereditary sensory and autonomic, type 2A	Benign (1)	criteria provided, single submitter	Aug 22, 2023	RCV000986925.10
Generalized epilepsy with febrile seizures plus, type 7 Neuropathy, hereditary sensory and autonomic, type 2A	Benign (1)	criteria provided, single submitter	Jan 30, 2024	RCV001083229.16
Primary erythromelalgia	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001094589.12
Inherited Erythromelalgia	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000281545.13
Paroxysmal extreme pain disorder	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000284837.13
Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000398464.13
not specified	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jul 20, 2017	RCV000218739.21
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Sep 3, 2019	RCV002415629.9
SCN9A-related disorder	Likely benign (1)	no assertion criteria provided	Oct 27, 2020	RCV004532638.2
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jun 1, 2024	RCV000416064.43
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Apr 05, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596991.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Likely benign (Jul 20, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000203531.7 First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 19763161‚ 21698661‚ 22826602 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN9A Number of individuals with the variant: 4 Zygosity: Single Heterozygote Sex: mixed
Likely benign (Jun 09, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001476868.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (11) PubMed: 24820863‚ 29176367‚ 19763161‚ 21698661‚ 22539570‚ 22826602‚ 30478917‚ 27301361‚ 31193310‚ 29961513‚ 27608006
Likely benign (Aug 19, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000297131.3 First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Neuropathy, hereditary sensory and autonomic, type 2A Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001136081.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023
Benign (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuropathy, hereditary sensory and autonomic, type 2A Generalized epilepsy with febrile seizures plus, type 7 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000559263.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024
Likely benign (Sep 03, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002724795.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000493391.33 First in ClinVar: Jan 30, 2017 Last updated: Oct 20, 2024	Comment: SCN9A: BS2 Number of individuals with the variant: 10
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Inherited Erythromelalgia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000418598.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Mar 28, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610459.1 First in ClinVar: Nov 04, 2017 Last updated: Nov 04, 2017
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Primary erythromelalgia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000418599.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 22826602‚ 21698661‚ 24820863‚ 22539570 Comment: 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, … (more) 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Paroxysmal extreme pain disorder Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000418595.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: 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, … (more) 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Channelopathy-associated congenital insensitivity to pain, autosomal recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000418597.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: 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, … (more) 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (May 12, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279166.10 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 19763161, 24820863, 24737233, 32707200, 22539570, 27301361, 28073787, 28235406, 23891399, 29176367, 27608006, 27916648, 28488083, 30478917, 31664448, 22826602, … (more) This variant is associated with the following publications: (PMID: 19763161, 24820863, 24737233, 32707200, 22539570, 27301361, 28073787, 28235406, 23891399, 29176367, 27608006, 27916648, 28488083, 30478917, 31664448, 22826602, 21698661) (less)
Pathogenic (Sep 01, 2014)	no assertion criteria provided Method: literature only	NEUROPATHY, SMALL FIBER Affected status: not provided Allele origin: germline	OMIM Accession: SCV000191928.2 First in ClinVar: Nov 15, 2014 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 22826602‚ 24820863‚ 28073787 Comment on evidence: In 3 unrelated patients with small fiber neuropathy (see 133020) and severe autonomic dysfunction, Han et al. (2012) identified a heterozygous c.2215A-G transition in exon … (more) In 3 unrelated patients with small fiber neuropathy (see 133020) and severe autonomic dysfunction, Han et al. (2012) identified a heterozygous c.2215A-G transition in exon 13 of the SCN9A gene, resulting in an ile739-to-val (I739V) substitution at a highly conserved residue in the transmembrane segment of domain II. The variant was not present in the 1000 Genomes Project database, but it was reported with a 0.5% frequency in the Exome Variant Server database and was found in 1.4% of Dutch control individuals. In vitro functional expression assays in rat neurons showed that the I739V mutation impaired channel slow inactivation in both dorsal root ganglion cells and sympathetic neurons of the superior cervical ganglion. The mutation rendered dorsal root ganglion neurons hyperexcitable and superior ganglion neurons hypoexcitable. Han et al. (2012) suggested that the effects of the mutation on 2 different types of neurons correlate with the symptoms of pain and autonomic dysfunction. Devigili et al. (2014) identified a heterozygous I739V mutation in the SCN9A gene in a woman, her sister, and their mother with small fiber neuropathy manifest as paroxysmal intense neuropathic itch attacks, mainly triggered by warmth and spicy food and followed by transient burning pain. All 3 patients showed preferential involvement of the proximal arms, trunk, and neck, and all had impaired superficial sensation in the affected body area. In the 3 affected members of the family reported by Devigili et al. (2014), Martinelli-Boneschi et al. (2017) identified a heterozygous missense (R2162S) variant in the COL6A5 gene (611916). The variant, which was found by whole-exome sequencing, segregated with the disorder in the family; it was present at a low frequency in the ExAC and gnomAD databases (2.5 x 10(-5)). Functional studies of the R2162S variant were not performed, but the authors postulated that the COL6A5 variant may have contributed to the phenotype. Martinelli-Boneschi et al. (2017) noted that the mother in the family developed dysautonomic symptoms, including cardiovascular and sympathetic cholinergic impairment, which may have been related to the SCN9A mutation. In addition, none demonstrated length-dependent distribution of symptoms that usually occurs in small fiber neuropathy, and 1 of the 3 patients did not have small fiber neuropathy on skin biopsy. The itch in all patients responded well to gabapentin treatment. The contribution of each variant to the phenotype was unclear. (less)
Likely benign (Oct 27, 2020)	no assertion criteria provided Method: clinical testing	SCN9A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004756534.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy.	Gomis-Pérez C	Epilepsia	2019	PMID: 30478917
Infantile Epileptic Encephalopathy With Multiple Genetic Mutations: How Important are Variants of Undetermined Significance?	Almomen M	Seminars in pediatric neurology	2018	PMID: 29961513
Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.	Blesneac I	Pain	2018	PMID: 29176367
Compound heterozygosity with PRRT2: Pushing the phenotypic envelope in genetic epilepsies.	El Achkar CM	Epilepsy & behavior case reports	2017	PMID: 31193310
COL6A5 variants in familial neuropathic chronic itch.	Martinelli-Boneschi F	Brain : a journal of neurology	2017	PMID: 28073787
Roles of Voltage-Gated Tetrodotoxin-Sensitive Sodium Channels NaV1.3 and NaV1.7 in Diabetes and Painful Diabetic Neuropathy.	Yang L	International journal of molecular sciences	2016	PMID: 27608006
Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases.	Tšuiko O	Human reproduction (Oxford, England)	2016	PMID: 27301361
Paroxysmal itch caused by gain-of-function Nav1.7 mutation.	Devigili G	Pain	2014	PMID: 24820863
Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy.	Han C	Brain : a journal of neurology	2012	PMID: 22826602
Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability.	Han C	Neurology	2012	PMID: 22539570
Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy.	Faber CG	Annals of neurology	2012	PMID: 21698661
A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.	Singh NA	PLoS genetics	2009	PMID: 19763161
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN9A	-	-	-	-
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Text-mined citations for rs182650126 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 15, 2024

ClinVar Genomic variation as it relates to human health

NM_001365536.1(SCN9A):c.2248A>G (p.Ile750Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs182650126 ...