NM_001365536.1(SCN9A):c.1604C>T (p.Ser535Leu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 3, 2019
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:: RCV000757742.11

Allele description [Variation Report for NM_001365536.1(SCN9A):c.1604C>T (p.Ser535Leu)]

NM_001365536.1(SCN9A):c.1604C>T (p.Ser535Leu)

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.1604C>T (p.Ser535Leu)

HGVS:

NC_000002.12:g.166284823G>A
NG_012798.1:g.96165C>T
NM_001365536.1:c.1604C>TMANE SELECT
NM_002977.4:c.1604C>T
NP_001352465.1:p.Ser535Leu
NP_002968.1:p.Ser535Leu
NP_002968.1:p.Ser535Leu
NP_002968.2:p.Ser535Leu
LRG_369t1:c.1604C>T
LRG_369:g.96165C>T
LRG_369p1:p.Ser535Leu
NC_000002.11:g.167141333G>A
NM_002977.2:c.1604C>T
NM_002977.3:c.1604C>T

Protein change:

S535L

Links:

dbSNP: rs201354321

NCBI 1000 Genomes Browser:

rs201354321

Molecular consequence:

NM_001365536.1:c.1604C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002977.4:c.1604C>T - 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
SCV000886081	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Sep 26, 2017)	germline	clinical testing	Citation Link,
SCV001819951	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 3, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000886081

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Sep 26, 2017)

germline

clinical testing

Citation Link,

SCV001819951

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 3, 2019)

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000886081.1

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

Description

The p.Ser535Leu variant (rs201354321) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.002 percent (identified on 4 out of 260,912 chromosomes). The serine at position 535 is highly conserved considering 12 species (Alamut v2.9.0) and computational analyses of the effects of the p.Ser535Leu variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Ser535Leu variant with certainty.

#	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, SCV001819951.1

#	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 a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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: Sep 29, 2024

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