chr3-38566558-C-T

Position:

• chr3-38566558-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_000335.5(SCN5A):​c.3688G>A​(p.Glu1230Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 0.327

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 6 ACMG points.

• PM1: In a topological_domain Extracellular (size 12) in uniprot entity SCN5A_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 3-38566558-C-T is Pathogenic according to our data. Variant chr3-38566558-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67812.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Pathogenic=1}. Variant chr3-38566558-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3691G>A	p.Glu1231Lys	missense_variant	21/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3688G>A	p.Glu1230Lys	missense_variant	21/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3691G>A	p.Glu1231Lys	missense_variant	21/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3688G>A	p.Glu1230Lys	missense_variant	21/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250008 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135484

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 SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727102

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2022	This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (Invitae). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67812). This variant is present in population databases (rs199473598, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1231 of the SCN5A protein (p.Glu1231Lys). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2011	p.Glu1231Lys in the SCN5A gene; disease-causing mutation (Tester D et al. 2008). TheG>A nucleotide substitution in exon 21 of the SCN5A gene, results in replacement of the normal Glutamic acid codon (GAG) with a Lysine codon (AAG) at amino acid position 1231 in the cardiac sodium voltage-gated channel, type V-a. This missense change is denoted p.Glu1231Lys (aka E1231K) at the protein level and c.3691 G>A at the cDNA level. The Glu1231Lys mutation has been reported in association with LQTS (Tester D et al. 2008). Tester et al. reported Glu1231Lys in one patient with LQTS and did not observe it in more than 1,500 control alleles. This mutation also was not observed in up to 400 control alleles from individuals of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphsim. Glu1231Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine residue at a position that is class conserved. Furthermore, mutations in surrounding codons (Tyr1228His, Arg1232Gln, Lys1236Arg, Lys1236Asn, Leu1239Pro) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s). -

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:15840476). 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	0.093
CardioboostCm	Benign	0.0093
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	-0.025	.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.37	T;T;T;T;T;T;T;T;T
Polyphen		0.021	B;B;.;B;.;B;B;.;.
Vest4		0.78
MutPred		0.82		Gain of methylation at E1231 (P = 0.0193);.;Gain of methylation at E1231 (P = 0.0193);Gain of methylation at E1231 (P = 0.0193);.;Gain of methylation at E1231 (P = 0.0193);.;.;.;
MVP		0.96
MPC		0.62
ClinPred		0.44	T
GERP RS		4.5
Varity_R		0.34
gMVP		0.84

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: rs199473598; hg19: chr3-38608049; COSMIC: COSV61141160;