NM_000335.5(SCN5A):c.1844G>A (p.Gly615Glu) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 16, 2021
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:: RCV000151792.21

Allele description [Variation Report for NM_000335.5(SCN5A):c.1844G>A (p.Gly615Glu)]

NM_000335.5(SCN5A):c.1844G>A (p.Gly615Glu)

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.1844G>A (p.Gly615Glu)

Other names:

p.G615E:GGA>GAA

HGVS:

NC_000003.12:g.38603758C>T
NG_008934.1:g.50915G>A
NM_000335.5:c.1844G>AMANE SELECT
NM_001099404.2:c.1844G>A
NM_001099405.2:c.1844G>A
NM_001160160.2:c.1844G>A
NM_001160161.2:c.1844G>A
NM_001354701.2:c.1844G>A
NM_198056.3:c.1844G>A
NP_000326.2:p.Gly615Glu
NP_000326.2:p.Gly615Glu
NP_001092874.1:p.Gly615Glu
NP_001092875.1:p.Gly615Glu
NP_001153632.1:p.Gly615Glu
NP_001153633.1:p.Gly615Glu
NP_001341630.1:p.Gly615Glu
NP_932173.1:p.Gly615Glu
NP_932173.1:p.Gly615Glu
LRG_289t1:c.1844G>A
LRG_289t2:c.1844G>A
LRG_289:g.50915G>A
LRG_289p1:p.Gly615Glu
LRG_289p2:p.Gly615Glu
NC_000003.11:g.38645249C>T
NM_000335.4:c.1844G>A
NM_198056.2:c.1844G>A
Q14524:p.Gly615Glu

Protein change:

G615E

Links:

UniProtKB: Q14524#VAR_026358; dbSNP: rs12720452

NCBI 1000 Genomes Browser:

rs12720452

Molecular consequence:

NM_000335.5:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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ZBTB6 [Meleagris gallopavo]
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Gene ID:100550000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000200248	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Feb 11, 2019)	germline	clinical testing	PubMed (20) [See all records that cite these PMIDs] 24613995, 11997281, 18071069, 15840476, 19716085, 14760488, 27435932, 27930701, 20486126, 26669661, 22378279, 23631430, 25650408, 23861362, 27153395, 19841300, 28412158, 28798025, 29874177, 24033266
SCV000920188	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 16, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11997281, 23631430, 25637381, 27930701, 27435932, 24613995, 31737537, 28412158, 32516855, 31262209 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000200248

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Feb 11, 2019)

germline

clinical testing

PubMed (20)
[See all records that cite these PMIDs]

SCV000920188

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 16, 2021)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cardiac sodium channel gene variants and sudden cardiac death in women.

Albert CM, Nam EG, Rimm EB, Jin HW, Hajjar RJ, Hunter DJ, MacRae CA, Ellinor PT.

Circulation. 2008 Jan 1;117(1):16-23. Epub 2007 Dec 10.

PubMed [citation]

PMID:: 18071069

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]

PMID:: 15840476

See all PubMed Citations (24)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000200248.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (20)

Description

The p.Gly615Glu variant in SCN5A has been reported in at least 10 individuals with LQTS, 4 individuals with sudden death, 1 individual with Brugada syndrome, 1 individual with HCM and 1 individual with delayed enhancement in LV (Albert 2008, Beyder 2010, Itoh 2016, Kapplinger 2009, Le Scouarnec 2015, Lieve 2013, Methner 2016, Ng 2013, Paulussen 2004, Sanchez 2016, Tester 2005, Yang 2002). In vitro functional studies provide some evidence that the p.Gly615Glu variant may impact protein function (Beyder 2014, Albert 2008). However, these types of assays may not accurately represent biological function. This variant has also been reported in ClinVar (Variation ID 67691) and has been identified in 50/106156 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12720452). Computational prediction tools and conservation analysis suggest that the p.Gly615Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to conflicting data, the p.Gly615Glu variant is uncertain. ACMG/AMP Criteria applied: PS4, PP3, PS3_S, BS1 (Richards 2015).

#	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		3	not provided	3	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920188.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant summary: SCN5A c.1844G>A (p.Gly615Glu) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 199960 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome With Sudden Cardiac Death phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1844G>A has been reported in the literature in multiple LQTS patients, including some diagnosed with Sudden Cardiac Death and LQTS triggered by quinidine (e.g. Lieve_2013, Sanchez_2016, Methner_2016, Anderson_2017, Marschall_2019). In addition, this variant was also reported in one proband with neonatal DCM, one family member with episode of chest pain with normal QT interval, and three aymptomatic family members with prolonged QT interval (Hawley_2020). These data do not provide unequivocal conclusions about association of the variant with LQTS or other diseases. Functional studies have reported conflicting results with no effect on the peak amplitude of voltage-gated sodium current (Yang_2002), positive shifts in voltage dependence of activation, with altered activation kinetics and slower activation than wildtype associated with this variant (Beyder_2014), and disruptions in mechanosensitivity (Strege_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=2, VUS n=8). Based on the evidence outlined above, the variant was classified as VUS-possibly 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

Last Updated: Nov 10, 2024

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