NM_000335.5(SCN5A):c.486C>T (p.Tyr162=) AND not specified

Germline classification:: Benign/Likely benign (4 submissions)
Last evaluated:: Jun 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:: RCV000151807.20

Allele description [Variation Report for NM_000335.5(SCN5A):c.486C>T (p.Tyr162=)]

NM_000335.5(SCN5A):c.486C>T (p.Tyr162=)

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.486C>T (p.Tyr162=)

HGVS:

NC_000003.12:g.38620968G>A
NG_008934.1:g.33705C>T
NM_000335.5:c.486C>TMANE SELECT
NM_001099404.2:c.486C>T
NM_001099405.2:c.486C>T
NM_001160160.2:c.486C>T
NM_001160161.2:c.486C>T
NM_001354701.2:c.486C>T
NM_198056.3:c.486C>T
NP_000326.2:p.Tyr162=
NP_001092874.1:p.Tyr162=
NP_001092875.1:p.Tyr162=
NP_001153632.1:p.Tyr162=
NP_001153633.1:p.Tyr162=
NP_001341630.1:p.Tyr162=
NP_932173.1:p.Tyr162=
NP_932173.1:p.Tyr162=
LRG_289t1:c.486C>T
LRG_289:g.33705C>T
LRG_289p1:p.Tyr162=
NC_000003.11:g.38662459G>A
NM_198056.2:c.486C>T
p.Tyr162Tyr

Links:

dbSNP: rs45489099

NCBI 1000 Genomes Browser:

rs45489099

Molecular consequence:

NM_000335.5:c.486C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001099404.2:c.486C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001099405.2:c.486C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001160160.2:c.486C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001160161.2:c.486C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354701.2:c.486C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_198056.3:c.486C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000200273	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Mar 19, 2012)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000231242	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Sep 25, 2014)	germline	clinical testing	Citation Link,
SCV001363136	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jun 3, 2019)	germline	clinical testing	Citation Link,
SCV001924972	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000200273.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

Description

p.Tyr162Tyr in Exon 05 of SCN5A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence and has been identified in 0.9% (28/3212) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs45489099).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	5	not provided

From Eurofins Ntd Llc (ga), SCV000231242.5

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

#	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		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363136.1

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

Description

Variant summary: SCN5A c.486C>T alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 248802 control chromosomes. The observed variant frequency is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.486C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A, p.Val142Ile) at our laboratory providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign (n=1). Based on the evidence outlined above, the variant was 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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001924972.1

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

#	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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