rs199473114

Positions:

• chr3-38604862-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000335.5(SCN5A):​c.1385A>C​(p.Glu462Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E462K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 5.97

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38604863-C-T 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 4.8279 (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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1385A>C	p.Glu462Ala	missense_variant	11/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1385A>C	p.Glu462Ala	missense_variant	11/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1385A>C	p.Glu462Ala	missense_variant	11/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1385A>C	p.Glu462Ala	missense_variant	11/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461430 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 462 of the SCN5A protein (p.Glu462Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 28412158). ClinVar contains an entry for this variant (Variation ID: 67661). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 25904541, 28412158). This variant disrupts the p.Glu462 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 19841300, 24721456), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2020	Reported in association with Long QT syndrome (Kapplinger et al., 2009; Webster et al., 2019); however, additional clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67661; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In vitro functional studies suggested that E462A variant demonstrates the channel function similar to wild-type (Kapplinger al., 2015); This variant is associated with the following publications: (PMID: 19716085, 25904541, 28412158, 31395126) -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 06, 2021

- -

Long QT syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 01, 2024

This sequence change in SCN5A is predicted to replace glutamic acid with alanine at codon 462, p.(Glu462Ala). The glutamic acid residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in a cytoplasmic region. There is a large physicochemical difference between glutamic acid and alanine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0005% (6/1,111,776 alleles) in the European (non-Finnish) population, which is consistent with SCN5A-related cardiac disorders. This variant has been reported in at least two individuals with long QT syndrome (PMID: 25904541, 31395126). The variant has a normal electrophysiological status in a patch-clamp assay with limited validation (PMID: 25904541). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.771). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BS3_Supporting, PM2_Supporting, PP3, PS4P. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 30, 2019

This missense variant replaces glutamic acid with alanine at codon 462 of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown that this variant does not affect sodium channel function (PMID: 28412158). However, clinical relevance of this observation is not clear. This variant has been reported in two individuals affected with long QT syndrome (PMID: 25904541, 28412158) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
CardioboostCm	Uncertain	0.27
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.4	.;M;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T
Polyphen		0.96	P;P;.;P;.;P;D;.;.
Vest4		0.87
MutPred		0.68		Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);Gain of MoRF binding (P = 0.0301);
MVP		0.87
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.28
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199473114; hg19: chr3-38646353;