3-38551012-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP2BP4_StrongBS2
The NM_001099404.2(SCN5A):c.5360G>A(p.Ser1787Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000495 in 1,614,018 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign 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. S1787T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.5360G>A | p.Ser1787Asn | missense_variant | 28/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.5357G>A | p.Ser1786Asn | missense_variant | 28/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.5360G>A | p.Ser1787Asn | missense_variant | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.5357G>A | p.Ser1786Asn | missense_variant | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000618 AC: 94AN: 152124Hom.: 4 Cov.: 31
GnomAD3 exomes AF: 0.000905 AC: 227AN: 250882Hom.: 2 AF XY: 0.000788 AC XY: 107AN XY: 135834
GnomAD4 exome AF: 0.000482 AC: 705AN: 1461894Hom.: 4 Cov.: 35 AF XY: 0.000480 AC XY: 349AN XY: 727248
GnomAD4 genome ? AF: 0.000618 AC: 94AN: 152124Hom.: 4 Cov.: 31 AF XY: 0.000673 AC XY: 50AN XY: 74294
ClinVar
Submissions by phenotype
not provided Benign:3Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:10973849;PMID:15851227;PMID:16414944;PMID:19841300;PMID:20129283;PMID:22378279). - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2020 | This variant is associated with the following publications: (PMID: 20129283, 22378279, 26159999, 28988457, 30669290, 15851227, 23503384, 25923670, 16414944, 10973849, 24055113, 25637381, 27930354, 11463728, 22677073, 14753626, 28069705, 22373669, 27153395, 23861362, 30847666) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | SCN5A: PP3, BS2 - |
Long QT syndrome Uncertain:1Benign:2
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Brugada syndrome 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 22, 2021 | Variant summary: SCN5A c.5360G>A (p.Ser1787Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 395574 control chromosomes, predominantly at a frequency of 0.02 within the Ashkenazi Jewish (ASJ) subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within ASJ control individuals in the gnomAD database is approximately 200-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism. c.5360G>A has been reported in the literature in individuals affected with Arrhythmia (Splawski_2000, Zaklyazminskaya_2013), however it was also found in several healthy controls (e.g. Kapplinger_2010, Ackerman_2004, Ng_2013, Refsgaard_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. One publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the molecular phenotype of the S1787N variant might depend upon both the splice variant background in which it is expressed and on the intracellular pH, i.e. the channel properties of the S1787N in the Q1077del background were altered under more acidic conditions (Hu_2015). These data however, do not allow convincing conclusions about the variant effect. Nine submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), likely benign (n=2) or benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 10, 2019 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
Pathogenic, flagged submission | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Dilated cardiomyopathy 1E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Progressive familial heart block, type 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Sick sinus syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2018 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Cardiac arrhythmia Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at