3-38613782-G-C

Position:

• chr3-38613782-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000335.5(SCN5A):​c.664C>G​(p.Arg222Gly) variant causes a missense change. 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. R222Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.94

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 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38613781-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.987
• PP5: Variant 3-38613782-G-C is Pathogenic according to our data. Variant chr3-38613782-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201440.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.664C>G	p.Arg222Gly	missense_variant	6/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.703+193C>G		intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000423572.7	c.664C>G	p.Arg222Gly	missense_variant	6/28	1	NM_000335.5	A1
SCN5A	ENST00000413689.6	c.703+193C>G		intron_variant		5	NM_001099404.2	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 222 of the SCN5A protein (p.Arg222Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 30116708). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201440). 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 disruptive. This variant disrupts the p.Arg222 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19716085, 21483645, 22766342, 22999724, 25210054). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2012	p.Arg222Gly (CGA>GGA): c.664 C>G in exon 6 of the SCN5A gene (NM_198056.2 )The Arg222Gly variant in the SCN5A gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Arg222Gly results in a non-conservative amino acid substitution of a positively charged Arginine with a non-polar Glycine at a residue that is conserved across species. In silico analysis predicts Arg222Gly is probably damaging to the protein structure/function. A different missense change at the same position (Arg222Gln) has been reported in association with different phenotypes. Arg222Gln was reported to co-segregate with a dilated cardiomyopathy phenotype in one family, while Arg222Gln has also been reported in an individual with LQTS (Hershberger R et al., 2008; Kapplinger J et al., 2009). The NHLBI ESP Exome Variant Server reports Arg222Gly was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, data from ethnically-matched control individuals were not available to assess for a population-specific benign variant.In summary, while the clinical significance of the Arg222Gly variant in the SCN5A gene is currently unknown, the evidence suggests it is likely disease-causing. The variant is found in BRUGADA panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.86
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.91		Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.95

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: rs794728849; hg19: chr3-38655273;