ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2989G>A (p.Ala997Thr) (rs137854609)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171570 SCV000050613 uncertain significance SUDDEN INFANT DEATH SYNDROME; Brugada syndrome 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151787 SCV000200239 uncertain significance not specified 2014-02-27 criteria provided, single submitter clinical testing The Ala997Thr variant in SCN5A has been reported in 1 adult with Brugada syndrom e (Kapplinger 2010, Conte 2014). Another variant at this position (Ala997Ser) ha s been reported in 1 infant with SIDS (absence in a large number of controls and in vitro functional studies supported pathogenicity though, though these assays may not accurately represent biological function; Ackerman 2001). Data from lar ge population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that this varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Ala997Thr variant.
GeneDx RCV000766794 SCV000235301 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The A997T variant has been reported in two individuals with a definitive or suspected diagnosis of Brugada syndrome (Krahn et al. 2009; Kapplinger et al., 2010; Conte et al., 2014). Ng et al. (2013) identified A997T as a secondary finding via exome sequencing of ClinSeq participants. The individual was subsequently found to have an abnormal EKG with sinus bradycardia and right atrial abnormality, and authors classified A997T as likely pathogenic (Ng et al. 2013). No segregation data have been published to our knowledge. The A997T variant has also been reported in one individual with irritable bowel syndrome (IBS) (Beyder et al., 2014). The A997T variant has been observed in 12/57,670 (0.02%) alleles in individuals of European background in large population cohorts (Lek et al., 2016). Additionally, this variant is classified in ClinVar as a variant of uncertain significance by three other clinical laboratories (SCV000200239.4, SCV000545040.2, SCV000747960.1; Landrum et al., 2016).Functional studies in HEK-293 cells expressing the A997T variant demonstrated a significant effect on channel function including a 98% reduction in peak channel current (Beyder et al., 2014). The loss of function phenotype was rescued by incubating the cells in mexiletine, an anti-arrhythmic drug shown previously to rescue SCN5A-related channel defects (Beyder et al., 2014). The A997T 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. Nevertheless, in silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000058541 SCV000545040 uncertain significance Brugada syndrome 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 997 of the SCN5A protein (p.Ala997Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs137854609, ExAC 0.02%). This variant has been reported in several individuals with suspected Brugada syndrome (PMID: 19597050, 20129283, 24681144, 29728395) and an individual with irritable bowel syndrome (PMID: 24613995). ClinVar contains an entry for this variant (Variation ID: 67771). Experimental studies have shown that this missense change reduces SCN5A activity (PMID: 24613995). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000058541 SCV000747960 uncertain significance Brugada syndrome 2016-08-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766794 SCV001153867 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001145179 SCV001305827 uncertain significance Paroxysmal familial ventricular fibrillation 1 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001145180 SCV001305828 uncertain significance Long QT syndrome 3 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001145181 SCV001305829 uncertain significance Dilated cardiomyopathy 1E 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001145182 SCV001305830 uncertain significance Sick sinus syndrome 1, autosomal recessive 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001147136 SCV001307919 uncertain significance Progressive familial heart block, type 1A 2017-04-28 criteria provided, single submitter clinical testing 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.
Color RCV001187859 SCV001354759 likely benign Arrhythmia 2019-01-08 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196613 SCV001367221 uncertain significance Myopathy; Meningioma; Cataract (disease); Osteoporosis; Hypertensive disorder 2019-08-20 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058541 SCV000090061 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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