3-38608209-A-G

Position:

• chr3-38608209-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001099404.2(SCN5A):​c.940T>C​(p.Tyr314His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Y314D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.57

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.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.940T>C	p.Tyr314His	missense_variant	8/28	ENST00000413689.6
SCN5A	NM_000335.5	c.940T>C	p.Tyr314His	missense_variant	8/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.940T>C	p.Tyr314His	missense_variant	8/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.940T>C	p.Tyr314His	missense_variant	8/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 23, 2017	In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant identified in the SCN5A gene is located in the transmembrane spanning DI-S5/S6 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. 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. ClinVar contains an entry for this variant (Variation ID: 201574). This sequence change replaces tyrosine with histidine at codon 314 of the SCN5A protein (p.Tyr314His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2017	The Tyr314His variant in the SCN5A gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Tyr314His results in a non-conservative substitution of a neutral, polar Tyrosine residue with a positively charged Histidine residue at a position that is conserved across species. Although in silico analysis predicts Tyr314His is probably benign to the protein structure/function (Adzhubei 2010; Schwarz 2011), other mutations affecting nearby residues (Leu315Pro, Lys317Asn) have been reported in association with Brugada syndrome, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Tyr314His was not observed in approximately 3,000 individuals from European and African American backgrounds. The variant is found in LQT panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
CardioboostCm	Benign	0.0065
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.4	.;L;.;.;.;L;.;.;.
MutationTaster	Benign	0.92	N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.056	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;P;.;D;.;P;D;.;.
Vest4		0.81
MutPred		0.68		Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);
MVP		0.85
MPC		1.3
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.14
gMVP		0.98

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: rs794728925; hg19: chr3-38649700; COSMIC: COSV61132562;