rs199473045

chr3-38633228-C-Achr3-38633228-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_001099404.2(SCN5A):c.80G>T(p.Arg27Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,972 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. R27H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 24 pathogenic changes around while only 8 benign (75%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38633228-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.80G>T	p.Arg27Leu	missense_variant	2/28	ENST00000413689.6
SCN5A	NM_000335.5	c.80G>T	p.Arg27Leu	missense_variant	2/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.80G>T	p.Arg27Leu	missense_variant	2/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.80G>T	p.Arg27Leu	missense_variant	2/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248780 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135034

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: 0.0000654

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: 1460972 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 726798

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000163 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 25, 2022

This missense variant replaces arginine with leucine at codon 27 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
CardioboostArm	Uncertain	0.13
CardioboostCm	Benign	0.016
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D;.;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.050	T;D;D;T;D;D;D;D;D;D;.
Polyphen		0.88	P;D;.;P;.;P;P;.;.;.;.
Vest4		0.75
MutPred		0.64		Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);
MVP		0.87
MPC		1.0
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.63
gMVP		0.69

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: rs199473045; hg19: chr3-38674719;