chr3-38603840-GGAGGGC-G

Variant names:

• chr3-38603840-GGAGGGC-G
• rs397517953
• NM_001099404.2:c.1756_1761delGCCCTC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4 BP6 BS1

The NM_001099404.2(SCN5A):​c.1756_1761delGCCCTC​(p.Ala586_Leu587del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,612,764 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (1 hom.)
• Consequence: SCN5A NM_001099404.2 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 2.43
• Publications: 0 publications found

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001099404.2.
• BP6: Variant 3-38603840-GGAGGGC-G is Benign according to our data. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291. Variant chr3-38603840-GGAGGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48291.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000787 (115/1460468) while in subpopulation SAS AF = 0.00125 (108/86170). AF 95% confidence interval is 0.00106. There are 1 homozygotes in GnomAdExome4. There are 90 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1756_1761delGCCCTC	p.Ala586_Leu587del	conservative_inframe_deletion	Exon 12 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000149 AC: 37 AN: 248138 AF XY: 0.000216

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1460468 Hom.: 1 AF XY: 0.000124 AC XY: 90 AN XY: 726418

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00125 AC: 108 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111228

Other (OTH) AF: 0.0000663 AC: 4 AN: 60306

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Nov 01, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PM4 -

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala586_Leu587del variant in SCN5A has been reported in a case of SIDS and was absent from 364 controls (Amestad 2007). It has also been identified in 0.08% (4/4828) of South Asian chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant results in the deletion of an alanine (Ala) and a leucine (Leu) at position 586 and 587, but does not alter the amino acid reading frame. It is unclear how this deletion may impact the protein. In vitro functional studies showed that the variant did not exhibit a LongQT phenotype, however did have functional disturbances such as greater peak sodium densitites and changes in recovery from inactivation (Wang 2007 PMID: 17210841); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1. -

Oct 22, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28316956, 17210841, 17210839, 21215473, 27332903, 21167004, 25923670, 31043699) -

Aug 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome 1 Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:1

Apr 15, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes two amino acids from the linker region between transmembrane domains DI and DII of the SCN5A protein. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with sudden cardiac death (PMID: 27332903). This variant has also been identified in 36/245052 chromosomes (35/30726 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. -

Sudden unexplained death Benign:1

Nov 18, 2016

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The SCN5A Ala586_Leu587del has been previously reported in a case of Sudden Infant Death Syndrome (Arnestad et al, 2007). We identified this variant in a patient presenting with sudden unexplained death at 27yo. The allele frequency is 0.00015 in the Exome Aggregation Consortium (http://exac.broadinstitute.org/), which is higher than expected. Based on the relative rarity of arrhythmia syndromes causing unexplained SCD, we believe this variant could not cause disease. As a result we have classified this variant as 'likely benign'. -

Cardiovascular phenotype Benign:1

Sep 25, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=68/132	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397517953; hg19: chr3-38645331;