rs1060501140

Positions:

• chr3-38633096-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001099404.2(SCN5A):​c.212C>T​(p.Pro71Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P71A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.63

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 3 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 24 pathogenic changes around while only 9 benign (73%) 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23934883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.212C>T	p.Pro71Leu	missense_variant	2/28	ENST00000413689.6
SCN5A	NM_000335.5	c.212C>T	p.Pro71Leu	missense_variant	2/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.212C>T	p.Pro71Leu	missense_variant	2/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.212C>T	p.Pro71Leu	missense_variant	2/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459844 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 07, 2017

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant identified in the SCN5A gene is located in the cytoplasmic N-terminal 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. This sequence change replaces proline with leucine at codon 71 of the SCN5A protein (p.Pro71Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 04, 2023

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the N-terminal region of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant 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 role of this variant in disease conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Benign	0.0017
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;.;.;.;T;.;.;.;T
Eigen	Benign	0.094
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	.;T;T;T;T;T;T;.;T;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.57	.;N;.;.;.;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	2.3	N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.40	T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.81	T;T;T;T;T;T;T;T;T;T
Polyphen		0.24	B;B;.;B;.;D;P;.;.;.
Vest4		0.18
MutPred		0.30		Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);Loss of glycosylation at P71 (P = 0.0397);
MVP		0.77
MPC		0.53
ClinPred		0.66	D
GERP RS		4.7
Varity_R		0.033
gMVP		0.61

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: rs1060501140; hg19: chr3-38674587;