ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1579G>A (p.Gly527Arg) (rs763550164)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589940 SCV000589468 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing The G527R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the G527R 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. Moreover, this substitution occurs at a position where only amino acids with similar properties to Glycine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, although this variant has been seen in multiple individuals referred for cardiology testing at GeneDx, thus far, segregation data is limited or absent for these individuals and/or affected individuals harbored an additional pathogenic variant. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000589940 SCV000700019 uncertain significance not provided 2016-09-19 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.1579G>A (p.Gly527Arg) variant involves the alteration of a non-conserved nucleotide. This variant is located in the voltage-gated Na+ ion channel cytoplasmic domain (InterPro). 3/3 in silico tools predict a damaging outcome for this variant. This variant was found in 4/90200 control chromosomes at a frequency of 0.0000443, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.000025), suggesting this variant is possibly a benign polymorphism. However, with only four heterozygotes in ExAC it is uncertain whether this variant is benign as the phenotypes linked with this gene is often silent and has a variable age of onset and the pathogenic variants in this gene could have a reduced penetrance. The variant of interest has been reported in at least 1 affected individual without strong evidence for causality (Kapoor, 2016) and in 1 unaffected control from case-control studiy (Le Scouarnec,2015). It has been reported in a kidney carcinoma sample (Pickering CR et al 2014) and a skin carcinoma sample as a somatic occurrence (COSMIC). The variant has not been evaluated for functional impact by in vivo/vitro studies. Additional supporting evidence needed to classify this variant with confidence. Taken together, this variant is classified as variant of uncertain significance.
Invitae RCV000459544 SCV000545099 uncertain significance Brugada syndrome 2016-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 527 of the SCN5A protein (p.Gly527Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs763550164, ExAC 0.02%) but has not been reported in the literature in individuals with a SCN5A-related disease. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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