ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3206C>T (p.Thr1069Met) (rs199473187)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766797 SCV000235435 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The T1069M variant has been previously reported in at least two individuals in association with LQTS, and was absent from over 2,600 reference alleles (Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Kapplinger et al., 2015). Methner et al. (2016) also reported this variant in a one month old infant with sudden unexplained death, who also harbored additional variants in four other cardiac genes. Additionally, T1069M has been observed at GeneDx in two other individuals referred for cardiogenetic testing, who both harbored additional cardiogenetic variants, and in one other individual with DCM and a cardiac conduction disorder referred for exome sequencing. However, informative segregation data was unavailable for any of these published cases or the cases observed at GeneDx, and observation in these individuals alone, is not sufficient to determine the absolute pathogenicity of this variant. Furthermore, T1069M was reported in one individual from a cohort of control individuals with coronary artery disease but no history of cardiac arrest or ventricular arrhythmia (Stecker et al., 2006), although further clinical and family history details were not available. While T1069M was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, it was observed in approximately 0.10-0.14% of alleles from individuals of Latino ancestry in the 1000 Genomes Project and the Exome Aggregation Consortium, indicating it may be a rare benign variant in this population. Moreover, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, the T1069M 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. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001082100 SCV000545063 likely benign Brugada syndrome 2020-12-04 criteria provided, single submitter clinical testing
Mendelics RCV000987211 SCV001136460 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV001183486 SCV001349230 uncertain significance Arrhythmia 2020-10-14 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 1069 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 performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 37/246942 chromosomes (32/34364 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058554 SCV000090074 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183027 SCV000280472 uncertain significance not specified 2014-04-21 no assertion criteria provided clinical testing 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.Thr1069Met (T1069M; c.3206C>T) in exon 17 of the SCN5A gene (NM_198056.2) We do not believe there is enough evidence to call this variant “disease-causing” at this time. It may instead be a rare benign variant that is more common in individuals with Hispanic ancestry. It has only been published in one “case” of LQTS, and this individual was also Hispanic. Furthermore, there is no phenotype data available for that patient, and so we cannot confirm that the individual actually had LQTS. This variant has previously been reported in just one Hispanic individual (the ethnicity is important) who had genetic testing for LQTS through the Familion laboratory (Tester et al. 2005; Kapplinger et al. 2009, Kapa et al. 2009). There is no phenotype information available for this individual, and we cannot assume that they have a confirmed clinical diagnosis of LQTS. Of note, genetic testing for the 2500 Familion cases reported by Kapplinger et al (2009) have an unusually low yield of 36% (vs. 70% in cohorts with a firm diagnoses of long QT syndrome), which suggests that not all of these patients have a firm diagnosis. Also, these papers have a lack of clarity regarding which variants were seen with another pathogenic variant (9% of the cohort had multiple variants). This is a non-conservative amino acid change, resulting in the replacement of a polar Threonine with a nonpolar Methionine in interdomain linker II-III. The Threonine at this location is NOT conserved across vertebrate species, and in fact the default amino acid is a Methionine in alligators and in 2 species of bird. Variation at nearby residues (+/- 10 amino acids) has NOT been associated with LQTS except for at residue Ser1079, which may argue against the functional importance of this region of the protein: (HGMD professional version as of January 17, 2014; and GeneDx report). This site in the protein is also not conserved across paralogue proteins: http://cardiodb.org/Paralogue_Annotation/residue.php?gene=SCN5A&position=1069. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 0.993. In total the variant has been seen in 15 published controls or individuals from publicly available population datasets. The p.Thr1069Met variant is overrepresented among “Latino” individuals in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). It is present in 11 out of 5,749 Latinos in that database, which is an allele frequency of 0.1%. This estimates that ~2 out of every 1000 Latinos would carry the variant, which is a higher incidence than the overall estimated incidence of LQTS (1 in 2500 people). This variant is otherwise present in only 1 South Asian individual (out of 6,634) and 2 Caucasian individuals (out of 35,669). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. There is only one individual with this variant listed in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 3/26/2015, and this individual also has Mexican ancestry. The variant was not observed in published controls, including 1300 from Kapplinger et al. 2009 (143 of them Hispanic). There is also no variation at this residue 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 who are NOT ethnicity-matched to our patient (who has Hispanic ancestry). The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.

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