ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1993G>T (p.Ala665Ser) (rs756474485)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000771972 SCV000904926 uncertain significance Arrhythmia 2018-10-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the linker region between transmembrane domains DI and DII of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430), as well as in a control individual (PMID: 22216297). This variant has also been identified in 14/276636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000182993 SCV000235395 likely pathogenic not provided 2015-01-09 criteria provided, single submitter clinical testing p.Ala665Ser (GCA>TCA): c.1993 G>T in exon 13 of the SCN5A gene (NM_198056.2) The Ala665Ser variant in the SCN5A gene has not been published previously as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala665Ser represents a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Serine residue at a position that is highly conserved across species. In silico analysis predicts this change to be probably damaging to the structure/function of the protein. Mutations affecting nearby residues (Arg661Trp, Leu673Pro) have been reported in association with Brugada syndrome and LQTS, respectively, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ala665Ser 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.In summary, while Ala665Ser is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in BRUGADA panel(s).
Invitae RCV000548890 SCV000637096 uncertain significance Brugada syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 665 of the SCN5A protein (p.Ala665Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs756474485, ExAC 0.02%). This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430), but has also been observed in a control individual (PMID: 22216297). ClinVar contains an entry for this variant (Variation ID: 201467). This variant identified in the SCN5A gene is located in the interdomain linker DI/DII region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223785 SCV000280465 uncertain significance not specified 2014-07-30 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.Ala665Ser (c.1993G>T) in the SCN5A gene The Ala665Ser variant has been previously reported in just one individual clinically tested for LQTS, who also carried a second variant in a different LQTS gene, and there is no segregation data available. Lieve et al. (2013) reported it in a 10 year old male with a suspected diagnosis of LQTS and a family history of LQTS. He was diagnosed at age 7 and had a mean QTc of 494 msec. According to the paper, he also had a second variant: Arg82Trp in the KCNJ2 gene. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Alanine with a polar Serine. Alanine at this location is highly conserved across mammalian species. However, this residue varies in birds, reptiles, and fish. Variation at nearby residues (+/- 10) in humans has been associated with atrial fibrillation, LQTS, or Brugada syndrome, which may support the functional importance of this region of the protein: Glu655Lys, Arg661Trp, Leu673Pro (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Benign” with a score of 0.177. It is not present in ClinVar http://www.ncbi.nlm.nih.gov/clinvar/. In total the variant has not been seen in over 6800 published controls and individuals from publicly available population datasets. It was not observed in published controls: 200 Caucasian and 100 African American (Lieve et al. 2013). There is 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. 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. There is no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 2/2/2015.

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