NM_000335.5(SCN5A):c.3947T>G (p.Phe1316Cys) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 25, 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:: RCV002261176.14

Allele description [Variation Report for NM_000335.5(SCN5A):c.3947T>G (p.Phe1316Cys)]

NM_000335.5(SCN5A):c.3947T>G (p.Phe1316Cys)

Gene:

SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.3947T>G (p.Phe1316Cys)

Other names:

p.Phe1317Cys

HGVS:

NC_000003.12:g.38562428A>C
NG_008934.1:g.92245T>G
NM_000335.5:c.3947T>GMANE SELECT
NM_001099404.2:c.3950T>G
NM_001099405.2:c.3950T>G
NM_001160160.2:c.3947T>G
NM_001160161.2:c.3788T>G
NM_001354701.2:c.3947T>G
NM_198056.3:c.3950T>G
NP_000326.2:p.Phe1316Cys
NP_001092874.1:p.Phe1317Cys
NP_001092875.1:p.Phe1317Cys
NP_001153632.1:p.Phe1316Cys
NP_001153633.1:p.Phe1263Cys
NP_001341630.1:p.Phe1316Cys
NP_932173.1:p.Phe1317Cys
NP_932173.1:p.Phe1317Cys
LRG_289t1:c.3950T>G
LRG_289:g.92245T>G
LRG_289p1:p.Phe1317Cys
NC_000003.11:g.38603919A>C
NM_198056.2:c.3950T>G

Protein change:

F1263C

Links:

dbSNP: rs762546813

NCBI 1000 Genomes Browser:

rs762546813

Molecular consequence:

NM_000335.5:c.3947T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3950T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3950T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3947T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3788T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3947T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3950T>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000818844	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002542036	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004021649	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 6, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000818844

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 25, 2023)

germline

clinical testing

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

SCV002542036

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 14, 2021)

germline

clinical testing

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

SCV004021649

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 6, 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	not provided	not provided	not provided	not provided	not provided	clinical testing
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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000818844.3

#	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 phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1317 of the SCN5A protein (p.Phe1317Cys). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 570277). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs762546813, gnomAD 0.004%).

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV002542036.1

#	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, SCV004021649.1

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

Description

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; Has not been previously published as pathogenic or benign to our knowledge

#	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: Nov 3, 2024

ClinVar

Relating variation to medicine