3-38620843-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_001099404.2(SCN5A):c.611C>A(p.Ala204Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. A204V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 missense, splice_region
• Scores: Splicing: ADA: 0.8056
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 14) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38620843-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68028.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.611C>A	p.Ala204Glu	missense_variant, splice_region_variant	5/28	ENST00000413689.6
SCN5A	NM_000335.5	c.611C>A	p.Ala204Glu	missense_variant, splice_region_variant	5/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.611C>A	p.Ala204Glu	missense_variant, splice_region_variant	5/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.611C>A	p.Ala204Glu	missense_variant, splice_region_variant	5/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2019

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31930659) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostArm	Pathogenic	0.96
CardioboostCm	Benign	0.059
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D
Vest4		0.79
MVP		0.83
ClinPred		1.0	D
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.81
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.030		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: rs199473559; hg19: chr3-38662334;