NM_001365536.1(SCN9A):c.5491G>T (p.Val1831Phe) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 29, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001217435.5

Allele description [Variation Report for NM_001365536.1(SCN9A):c.5491G>T (p.Val1831Phe)]

NM_001365536.1(SCN9A):c.5491G>T (p.Val1831Phe)

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.5491G>T (p.Val1831Phe)

HGVS:

NC_000002.12:g.166199148C>A
NG_012798.1:g.181840G>T
NM_001365536.1:c.5491G>TMANE SELECT
NM_002977.4:c.5458G>T
NP_001352465.1:p.Val1831Phe
NP_002968.1:p.Val1820Phe
NP_002968.1:p.Val1820Phe
NP_002968.2:p.Val1820Phe
LRG_369t1:c.5458G>T
LRG_369:g.181840G>T
LRG_369p1:p.Val1820Phe
NC_000002.11:g.167055658C>A
NM_002977.2:c.5458G>T
NM_002977.3:c.5458G>T

Protein change:

V1820F

Links:

dbSNP: rs200196731

NCBI 1000 Genomes Browser:

rs200196731

Molecular consequence:

NM_001365536.1:c.5491G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002977.4:c.5458G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuropathy, hereditary sensory and autonomic, type 2A (HSAN2A)
Synonyms:: ACROOSTEOLYSIS, GIACCAI TYPE; ACROOSTEOLYSIS, NEUROGENIC; HSAN IIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0024309; MedGen: C2752089; Orphanet: 970; OMIM: 201300

Name:: Generalized epilepsy with febrile seizures plus, type 7 (GEFSP7)
Synonyms:: GEFS+, TYPE 7
Identifiers:: MONDO: MONDO:0013470; MedGen: C2751778; Orphanet: 36387; OMIM: 613863

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001389275	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001389275

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001389275.5

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

Description

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1820 of the SCN9A protein (p.Val1820Phe). This variant is present in population databases (rs200196731, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 946549). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN9A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Mar 5, 2024

ClinVar

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