chr3-38551231-T-C

Position:

• chr3-38551231-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The ENST00000423572.7(SCN5A):​c.5138A>G​(p.Asp1713Gly) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1713N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A ENST00000423572.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 8.01

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]

SCN5A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000423572.7
• 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 4.8279 (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, 0.983
• PP5: Variant 3-38551231-T-C is Pathogenic according to our data. Variant chr3-38551231-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67959.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr3-38551231-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5141A>G	p.Asp1714Gly	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5138A>G	p.Asp1713Gly	missense_variant	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5141A>G	p.Asp1714Gly	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5138A>G	p.Asp1713Gly	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2019

Identified in individuals with Brugada syndrome in published literature (Kapplinger et al., 2011; Amin et al., 2011; Kapplinger et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate reduction in the sodium channel current density (Amin et al., 2005; Meregalli et al., 2009).; This variant is associated with the following publications: (PMID: 19251209, 19606473, 21273195, 16266370, 25904541, 22373669, 20129283, 22581653, 28150151, 30728299, 30662450, 33131149) -

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 22, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MONDO#0024562), whereas gain of function is usually associated with long QT syndrome 3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene have autosomal dominant inheritance. SSS is usually caused by biallelic variants; however, heterozygotes may show symptoms (OMIM, PMID: 30364184). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a moderate amino acid change. (SP) 0602 - Variant is located in the ion transport domain (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Asp1714Asn) variant has been classified as a VUS by two clinical diagnostic laboratories (ClinVar). (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been classified as likely pathogenic by one clinical diagnostic laboratory (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant transcript transfected into HEK293T cells demonstrated significant reduction in current density at both room (21°C) and physiological (36°C) temperatures. However, only slow inactivation of the mutant channel was demonstrated at physiological temperature (PMID: 16266370). In addition, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Brugada 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 Brugada syndrome in the following publications (PMID:16266370;PMID:19251209;PMID:20129283). 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	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.94
MutPred		0.84		.;.;Gain of catalytic residue at G1712 (P = 0.0769);.;.;Gain of catalytic residue at G1712 (P = 0.0769);.;.;.;
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.99

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: rs199473628; hg19: chr3-38592722;