rs778522112

chr3-38603722-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.1880C>T(p.Pro627Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,510,996 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P627A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 3.79

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 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.1880C>T	p.Pro627Leu	missense_variant	12/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1880C>T	p.Pro627Leu	missense_variant	12/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1880C>T	p.Pro627Leu	missense_variant	12/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1880C>T	p.Pro627Leu	missense_variant	12/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000170 AC: 3 AN: 176382 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 93246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000464

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: 0.0000233

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 27 AN: 1358820 Hom.: 0 Cov.: 30 AF XY: 0.0000121 AC XY: 8 AN XY: 663670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000146

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000226

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00000846 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 15, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro627Leu (P627L; c.1880 C>T) in the SCN5A gene This variant has previously been reported in one unrelated individual with LQTS, with weak segregation data. Blaufox et al. (2012) found Pro627Leu in an LQT3 proband with a prolonged QTc interval. It was also present in the proband’s mother, who likewise had a prolonged QTc interval. Either this proband or the proband’s mother had suffered an aborted sudden cardiac death event (the language in the paper is unclear). Their ancestry is not specified. The study included 81% Caucasian, 11% African-American, and 8% Hispanic families. If the family was Hispanic, there is less ancestry-matched control data available. Variation at several nearby residues has been associated with arrhythmia syndromes, suggesting the functional importance of this protein region: Leu618Phe (LQT3), Leu619Phe (LQT3/Brugada), Arg620Cys (Brugada), Thr632Met (Brugada) (UniProtKB; IRCCS Fondazione Salvatore Maugeri database; testing report referencing HGMD database). This is a conservative amino acid change, resulting in the replacement of a nonpolar, sterically-constrained proline with a nonpolar leucine residue. The proline at this location is highly conserved across mammalian species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In total the variant has not been seen in >6500 published controls and individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. (Our patient’s ancestry is Hispanic.) No variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). It is not found in 1000 genomes (http://browser.1000genomes.org/Homo_sapiens/Search/New?db=core) as of December 2, 2012. Blaufox et al. (2012) did not report controls. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper weak segregation data -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	Reported in a proband with sudden death and also identified in this individual's mother; the mother was reported to have QTc prolongation, although no additional details were provided (Blaufox et al., 2012); Reported in an individual with HCM, severe right ventricular hypertrophy, and no noted arrhythmia who was found to harbor several additional cardiogenetic variants in genes associated with her phenotype (Guo et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Functionals studies demonstrated that p.(P627L) expressed in HEK-293 cells resulted in an electrophysiological phenotype similar to the wildtype; nevertheless, it is not clear how well these studies reproduce in vivo conditions (Kapplinger et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27566755, 22360817, 28323875, 25904541) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 627 of the SCN5A protein (p.Pro627Leu). This variant is present in population databases (rs778522112, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 22360817, 28323875). ClinVar contains an entry for this variant (Variation ID: 201577). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 25904541). 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. -

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces proline with leucine at codon 627 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). A functional study has indicated that this missense does not affect sodium channel function (PMID: 25904541). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 22360817, 27566755), in an individual affected with idiopathic dilated cardiomyopathy (Rodriguez-Garcia et al., 2011), and in two individuals affected with hypertrophic cardiomyopathy who also carried another pathogenic variant in the DSP or MYH7 genes (PMID: 28323875). This variant has been identified in 3/176382 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 24, 2023	This missense variant replaces proline with leucine at codon 627 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). A functional study has indicated that this missense does not affect sodium channel function (PMID: 25904541). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 22360817, 27566755), in an individual affected with idiopathic dilated cardiomyopathy (Rodriguez-Garcia et al., 2011), and in two individuals affected with hypertrophic cardiomyopathy who also carried another pathogenic variant in the DSP or MYH7 genes (PMID: 28323875). This variant has been identified in 3/176382 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. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2020

The p.P627L variant (also known as c.1880C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1880. The proline at codon 627 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with a QTc interval of 427ms and in her mother, who was reported to have a prolonged QTc interval (Blaufox AD et al. Am. J. Cardiol., 2012 May;109:1459-65). In addition, this alteration has been reported in a cohort of long QT syndrome patients (Wilde AA et al. Circulation, 2016 Sep;134:872-82), as well as in an individual with hypertrophic cardiomyopathy who also had variants in other cardiac-related genes (Guo X et al. PLoS ONE, 2017 Mar;12:e0174118). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
CardioboostArm	Benign	0.000011
CardioboostCm	Benign	0.0011
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T
Polyphen		0.91	P;P;.;P;.;D;P;.;.
Vest4		0.45
MutPred		0.23		Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);
MVP		0.80
MPC		0.55
ClinPred		0.84	D
GERP RS		4.1
Varity_R		0.069
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs778522112; hg19: chr3-38645213;