NM_001099404.2:c.3512G>A

Variant names:

• chr3-38575451-C-T
• rs878855289
• NM_001099404.2:c.3512G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001099404.2(SCN5A):​c.3512G>A​(p.Gly1171Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN5A NM_001099404.2 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.827

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 6 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.7729 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3512G>A	p.Gly1171Asp	missense_variant, splice_region_variant	Exon 20 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3509G>A	p.Gly1170Asp	missense_variant, splice_region_variant	Exon 20 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3512G>A	p.Gly1171Asp	missense_variant, splice_region_variant	Exon 20 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3509G>A	p.Gly1170Asp	missense_variant, splice_region_variant	Exon 20 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.05e-7 AC: 1 AN: 1417976 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698182

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: 0.00

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 1 Uncertain:1

-

Roden Lab, Vanderbilt University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38575451-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.01; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data. -

not provided Uncertain:1

Feb 29, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN5A-related disease. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine with aspartic acid at codon 1171 of the SCN5A protein (p.Gly1171Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostCm	Benign	0.0014
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;.;.;D;.;.;.
Eigen	Benign	0.096
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	.;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.8	.;.;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.083	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T
Polyphen		0.93	P;P;.;P;.;P;B;.;.
Vest4		0.53
MutPred		0.47		Gain of disorder (P = 0.0726);.;Gain of disorder (P = 0.0726);Gain of disorder (P = 0.0726);.;Gain of disorder (P = 0.0726);.;.;.;
MVP		0.57
MPC		0.25
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.28
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.010		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: rs878855289; hg19: chr3-38616942;