3-38581284-G-A

Position:

• chr3-38581284-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001099404.2(SCN5A):​c.2875C>T​(p.Leu959Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.98

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a repeat II (size 270) in uniprot entity SCN5A_HUMAN there are 47 pathogenic changes around while only 2 benign (96%) in NM_001099404.2
• 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 4.7729 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2875C>T	p.Leu959Phe	missense_variant	17/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2875C>T	p.Leu959Phe	missense_variant	17/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2875C>T	p.Leu959Phe	missense_variant	17/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.2875C>T	p.Leu959Phe	missense_variant	17/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Jan 14, 2022

This missense variant results in a substitution of leucine with phenylalanine at codon 959 of the SCN5A gene (transcript NM_001099404.1). This variant has been reported in ClinVar (463315) NM_000335.5 (SCN5A):c.2875C>T (p.Leu959Phe). The variant has not occurred in population databases. This position is conserved. In silico functional algorithms agree, predicting it as possibly damaging (PolyPhen) and deleterious (SIFT), but no functional studies were performed to confirm these predictions. The variant has not occurred in the literature associated with the disease. In conclusion, the available evidence is insufficient to determine the pathogenicity of this variant. Therefore, it is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2017

This variant identified in the SCN5A gene is located in the interdomain linker DII/DIII region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. In summary, this variant has uncertain impact on SCN5A function. The available evidence is currently insufficient to determine its role 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with a SCN5A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 959 of the SCN5A protein (p.Leu959Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the linker region between transmembrane domains DII and DIII 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. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.047	D;D;T;D;T;D;D;T;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.51
MutPred		0.69		Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);
MVP		0.88
MPC		0.24
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.59
gMVP		0.94

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: rs1329499714; hg19: chr3-38622775;