rs199473135

chr3-38599031-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001099404.2(SCN5A):c.1910C>T(p.Pro637Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P637P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.38

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1910C>T	p.Pro637Leu	missense_variant	13/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1910C>T	p.Pro637Leu	missense_variant	13/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1910C>T	p.Pro637Leu	missense_variant	13/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1910C>T	p.Pro637Leu	missense_variant	13/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant 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 (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 and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 67696). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 637 of the SCN5A protein (p.Pro637Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
CardioboostArm	Benign	0.00016
CardioboostCm	Benign	0.0027
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	22
Dann	Benign	0.97
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.40	N
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.050	T
MutationTaster	Benign	0.94	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.35	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B;B;.;.
Vest4		0.70
MutPred		0.77		Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);Gain of catalytic residue at P637 (P = 0.0217);
MVP		0.91
MPC		0.36
ClinPred		0.17	T
GERP RS		2.9
Varity_R		0.029
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199473135; hg19: chr3-38640522;