3-38603782-C-T

Variant names:

• chr3-38603782-C-T
• rs757119370
• NM_001099404.2:c.1820G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000335.5(SCN5A):​c.1820G>A​(p.Gly607Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,408,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.79

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1820G>A	p.Gly607Asp	missense_variant	Exon 12 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1820G>A	p.Gly607Asp	missense_variant	Exon 12 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1820G>A	p.Gly607Asp	missense_variant	Exon 12 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1820G>A	p.Gly607Asp	missense_variant	Exon 12 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000457 AC: 1 AN: 218670 Hom.: 0 AF XY: 0.00000853 AC XY: 1 AN XY: 117268

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000986

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 9 AN: 1408436 Hom.: 0 Cov.: 31 AF XY: 0.00000722 AC XY: 5 AN XY: 692932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.0000863

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 607 of the SCN5A protein (p.Gly607Asp). This variant is present in population databases (rs757119370, gnomAD 0.001%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 32470535). ClinVar contains an entry for this variant (Variation ID: 201460). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Jun 24, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly607Asp (GGC>GAC): c.1820 G>A in exon 12 of the SCN5A gene (NM_198056.2) A variant of unknown significance has been identified in the SCN5A gene. To our knowledge, the G607D variant has not been published as a mutation or as a benign polymorphism. The G607D variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G607D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is mostly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no definitively disease-causing mutations in a nearby residues have been reported in association with LQTS, suggesting this region of the protein may be tolerant to change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s). -

Cardiovascular phenotype Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G607D variant (also known as c.1820G>A), located in coding exon 11 of the SCN5A gene, results from a G to A substitution at nucleotide position 1820. The glycine at codon 607 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a long QT syndrome cohort and cardiomyopathy cohorts (Mahdieh N et al. Int J Cardiol, 2020 Oct;316:117-124; Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854; Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Cardiac arrhythmia Uncertain:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with aspartic acid at codon 607 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy ((PMID: 34935411) and another individual affected with long QT syndrome (PMID: 32470535). This variant has been identified in 1/218670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0088
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.0	.;N;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T
Polyphen		0.63	P;D;.;P;.;P;D;.;.
Vest4		0.69
MutPred		0.22		Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);
MVP		0.90
MPC		1.2
ClinPred		0.67	D
GERP RS		4.2
Varity_R		0.35
gMVP		0.75

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: rs757119370; hg19: chr3-38645273;