3-38550362-A-G

Position:

• chr3-38550362-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM5 PP2 BP4_Strong BP6 BS2

The NM_001099404.2(SCN5A):​c.6010T>C​(p.Phe2004Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,534,052 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F2004V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (13 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:19 O:1
• Conservation: PhyloP100: 0.0740

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38550362-A-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.7729 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005137861).
• BP6: Variant 3-38550362-A-G is Benign according to our data. Variant chr3-38550362-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48315.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=12, Benign=4, not_provided=1, Uncertain_significance=7}. Variant chr3-38550362-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.6010T>C	p.Phe2004Leu	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.6007T>C	p.Phe2003Leu	missense_variant	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.6010T>C	p.Phe2004Leu	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.6007T>C	p.Phe2003Leu	missense_variant	28/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 321 AN: 148396 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00100

Gnomad ASJ AF: 0.00410

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00129

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.000995

GnomAD3 exomes AF: 0.00198 AC: 389 AN: 195994 Hom.: 0 AF XY: 0.00208 AC XY: 215 AN XY: 103328

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.000949

Gnomad ASJ exome AF: 0.00369

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000885

Gnomad FIN exome AF: 0.000888

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00366 AC: 5071 AN: 1385538 Hom.: 13 Cov.: 31 AF XY: 0.00371 AC XY: 2520 AN XY: 678810

Gnomad4 AFR exome AF: 0.000284

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.0000514

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.000989

Gnomad4 NFE exome AF: 0.00429

Gnomad4 OTH exome AF: 0.00390

GnomAD4 genome AF: 0.00217 AC: 322 AN: 148514 Hom.: 0 Cov.: 33 AF XY: 0.00191 AC XY: 139 AN XY: 72592

Gnomad4 AFR AF: 0.000398

Gnomad4 AMR AF: 0.000999

Gnomad4 ASJ AF: 0.00410

Gnomad4 EAS AF: 0.000203

Gnomad4 SAS AF: 0.00151

Gnomad4 FIN AF: 0.00105

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.000983

Alfa AF: 0.00278 Hom.: 3

Bravo AF: 0.00227

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000497 AC: 2

ESP6500EA AF: 0.00311 AC: 26

ExAC AF: 0.00190 AC: 227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:19 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:9 Other:1

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 33131149, 31737537, 31043699, 31337358, 29672598, 29728395, 28359509, 27711072, 18456723, 17605181, 15851227, 20129283, 23414114, 23465283, 17210841, 22685113) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SCN5A: BP4 -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:15851227;PMID:17210839;PMID:18071069;PMID:18456723;PMID:19841300;PMID:17605181;PMID:20129283). -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 20, 2022	- -

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	Phe2004Leu in exon 28 of SCN5A: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (21/6776) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41311117). Phe2004Leu in exon 28 of SCN5A (rs41311117; allele frequency = 0.3%, 21/6776) ** -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2020	Variant summary: SCN5A c.6010T>C (p.Phe2004Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 213020 control chromosomes. The observed variant frequency is approximately 21- fold the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.6010T>C has been reported in the literature in individuals affected with sudden death, cardiomyopathies, Long-QT syndrome, and myocarditis (examples: Arnestead_2007, Belkaya_2017, Petrikin_2018, Marcondes_2018, Raju_2019, Mahdieh_2020), but also in healthy controls (examples: Kapplinger_2010, Ghouse_2017). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence indicating that the variant could affect SCN5A function (example: Wang_2007), however a large Danish population study did not identify an association between this variant and cardiac conditions (Ghouse_2017). 12 other ClinVar submitters (evaluation after 2014) cited the variant as uncertain significance (n=4) and benign/ likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign. -

Brugada syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Dec 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 20, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jan 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 03, 2021	- -

Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 20, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 20, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Progressive familial heart block, type 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 20, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Long QT syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 20, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Long QT syndrome;C1142166:Brugada syndrome Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Sick sinus syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 20, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2022

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. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 08, 2018

- -

Long QT syndrome 3;C4551804:Brugada syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

May 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	6.2
DANN	Benign	0.76
DEOGEN2	Benign	0.38	.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.67	.;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.0051	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	-0.34	.;.;.;.;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.63	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B;B;.;.
Vest4		0.10
MutPred		0.77		.;.;Loss of glycosylation at S2007 (P = 0.1612);.;.;Loss of glycosylation at S2007 (P = 0.1612);.;.;.;
MVP		0.55
MPC		0.60
ClinPred		0.0016	T
GERP RS		-1.6
Varity_R		0.056
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs41311117; hg19: chr3-38591853; COSMIC: COSV99048691; COSMIC: COSV99048691;