NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys) AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Jan 28, 2024
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:: RCV000183117.40

Allele description [Variation Report for NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys)]

NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys)

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.5347G>A (p.Glu1783Lys)

Other names:

p.E1784K:GAG>AAG

HGVS:

NC_000003.12:g.38551022C>T
NG_008934.1:g.103651G>A
NM_000335.5:c.5347G>AMANE SELECT
NM_001099404.2:c.5350G>A
NM_001099405.2:c.5296G>A
NM_001160160.2:c.5251G>A
NM_001160161.2:c.5188G>A
NM_001354701.2:c.5293G>A
NM_198056.3:c.5350G>A
NP_000326.2:p.Glu1783Lys
NP_001092874.1:p.Glu1784Lys
NP_001092875.1:p.Glu1766Lys
NP_001153632.1:p.Glu1751Lys
NP_001153633.1:p.Glu1730Lys
NP_001341630.1:p.Glu1765Lys
NP_932173.1:p.Glu1784Lys
NP_932173.1:p.Glu1784Lys
LRG_289t1:c.5350G>A
LRG_289t3:c.5350G>A
LRG_289:g.103651G>A
LRG_289p1:p.Glu1784Lys
NC_000003.11:g.38592513C>T
NM_001099404.1:c.5350G>A
NM_001099404.2:c.5350G>A
NM_198056.2:c.5350G>A
Q14524:p.Glu1784Lys

Protein change:

E1730K; GLU1784LYS

Links:

UniProtKB: Q14524#VAR_008959; OMIM: 600163.0008; dbSNP: rs137854601

NCBI 1000 Genomes Browser:

rs137854601

Molecular consequence:

NM_000335.5:c.5347G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5350G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5296G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5188G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5293G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5350G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235527	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 26, 2021)	germline	clinical testing	Citation Link,
SCV000280478	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (May 26, 2015)	germline	clinical testing
SCV000291817	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 10961955, 10973849, 12877697, 16379539, 18452873, 19841300, 21321465, 23631430, 24762805, 32533946, 10377081, 10727653, 18451998, 28492532
SCV000610392	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 26, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001248023	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2019)	germline	clinical testing	Citation Link,
SCV001446504	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001742855	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001924000	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	Pathogenic	germline	clinical testing
SCV001952109	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	6	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	30	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge.

Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E.

Circulation. 2000 Aug 29;102(9):945-7.

PubMed [citation]

PMID:: 10961955

Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT.

Circulation. 2000 Sep 5;102(10):1178-85.

PubMed [citation]

PMID:: 10973849

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000235527.14

#	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 (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have shown that E1784K results in SCN5A channel dysfunction by causing a persistent inward sodium current and a negative shift in steady-state inactivation (Wei et al., 1999; Deschenes et al., 2000; Makita et al., 2008; Abdelsayed et al., 2018); This variant is associated with the following publications: (PMID: 10727653, 18451998, 15840476, 31737537, 10377081, 24784157, 26131924, 21321465, 26831253, 27381756, 27677334, 28341781, 28412158, 28781849, 24871449, 10973849, 10961955, 19716085, 30364184, 29483621, 24762805, 19841300, 12877697, 16379539, 18452873, 23631430, 18508782, 30530868, 28976236, 28734073, 30662450, 31484910, 30193851, 32161207, 31447099, 32383558, 33131149)

#	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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280478.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	30	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1784Lys (c.5350G>A) in SCN5A (NM_001099404.1, ENST00000413689) Given the very strong case data, segregation data, and absence in individuals unselected for rare cardiac disease, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 30 unrelated cases of inherited channelopathy, and likely more than 52 cases (not including this patient's family). There is strong segregation data. Of note, the variant has been reported with a range of SCN5A-associated phenotypes including long QT syndrome type 3, Brugada syndrome, and conduction system disease (see Makita et al 2008 for multicenter data on the varied phenotype). Interestingly, the variant appears to be the most frequently identified long QT type 3 variant and the most frequently identified Brugada syndrome variant in a variety of cohorts. Makita et al (2008) report on 44 carriers of this variant across 15 families from multiple centers around the world (many likely overlap with prior reports). Most carriers had evidence of LQT3 (93%), 22% had evidence of Brugada syndrome, and 39% had sinus node dysfunction. All of the patients with evidence of Brugada also had evidence of long QT type 3. Half of the patients with Brugada had sinus node dysfunction. Only 2/44 carriers had no evidence of these three phenotypes, indicating high penetrance in this cohort. Of note, some carriers had evidence of all three phenotypes. Wei et al (1999) reported the variant in a Caucasian family with evidence of long QT syndrome (QTc 464-527 ms in affected relatives), sudden death at 13yo while at rest with native autopsy, sinus bradycardia, prominent unit(s) waves, ventricular ectopy during bradycardic episodes with occasional sinus pauses and one family member with "isoelectric ST segments". The authors are from Vanderbilt. They sequenced select exons of SCN5A in the family. The variant segregated with disease in 4 affected family members, including two first cousins. Priori et al (2000) reported on family with long QT syndrome and this variant. It isn't completely clear from the report, but it appears that three affected members of this family had this variant (QTc 496, 510, 520). A 12yo girl in this family had a resting QTc of 480 ms. With Flecainide provocation her QT shortened to 460 ms and ST segment elevation was provoked. Splawski et al (2000) observed the variant in 2 of 262 unrelated patients with long QT who underwent analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2. Patients were ascertained in Europe and North America (may overlap with reports by Priori's group, the US long QT registry, the international long QT registry). No ancestry, segregation, or individual phenotype data was provided. (Splawski et al 2000). Priori et al (2002) observed this variant in at least one patient with Brugada syndrome from a cohort of 130 unrelated patients with Brugada, presumably recruited in Italy (though that is not clear). Ackerman's group reported 3 unrelated patients with long QT syndrome and this variant Nemec et al 2003). They do not state where subjects were recruited, but all authors are form Mayo so presumably there. It appears that sequencing was done in Ackerman's research lab at Mayo. They note that one patient with this variant had microvoltage T wave alternans at baseline. In a subsequent paper they report an additional case, for a total of 4 (Tester et al 2005). Shim et al (2005) reported on a variant, E1783K, that appears to be the same variant, but with a slightly different number system. They observed it in two infants who underwent genetic testing at their laboratory at Boston University. Both had prolonged QT intervals and family history of sudden death in multiple family members. Behr et al (2008) identified the variant in a sudden death case from their London cohort. The variant was reported in 15 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Tester et al, Nemec et al since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Nakajima et al (2011) observed the variant in one of 30 Japanese probands with Brugada syndrome. Kapplinger et al (2010) reported 14 patients with this variant in their international compendium of SCN5A Brugada variants, likely overlapping with prior reports. Takahashi et al (2014) observed the variant 14 of 23 children found to have long QT syndrome through a school based ECG screening program in Okinawa, japan. There is only one submission from a clinical lab in ClinVar, Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust. They classify it as pathogenic. The variant occurs in the C terminus, just distal to the D4 transmembrane domain. Wei et al (1999) studied the effects of the variant in vitro and observed a defect in fast inactivation in xenopus oocytes. Makita et al (2008) report a negative shift in the voltage dependence of sodium channel inactivation and an increase in flecainide affinity for resting-state channels. They note these properties have been seen in other variants associated with mixed phenotypes. There is no variation at codon 1784 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of May 26th, 2015). Of note given both the patient's ancestry and the ancestry of some cases, this includes ~4300 East Asian individuals.

#	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		30	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000291817.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1784 of the SCN5A protein (p.Glu1784Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome, sick sinus syndrome, and/or Brugada syndrome (PMID: 10377081, 10727653, 10961955, 10973849, 12877697, 16379539, 18451998, 18452873, 19841300, 21321465, 23631430, 24762805). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9377). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 10377081, 10727653, 18451998). For these reasons, this variant has been classified as Pathogenic.

#	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 Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000610392.1

#	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	not provided	not provided	not provided	not provided		not provided	0.000179	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001248023.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	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		6	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446504.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742855.3

#	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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001924000.1

#	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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001952109.1

#	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: Dec 7, 2024

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