ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1735G>A (p.Gly579Arg) (rs199473128)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058450 SCV000089970 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:20129283;PMID:16414944;PMID:19841300).
Integrated Genetics/Laboratory Corporation of America RCV000058450 SCV000700021 uncertain significance not provided 2016-04-26 criteria provided, single submitter clinical testing Variant summary: This variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign/neutral outcome (SNP&GO not captured here due to low reliability index). This variant was observed in the large and broad cohorts of the ExAC project with observed allele frequency of 0.012% (14/ 120466), predominantly observed in South Asian with observed allele frequency of 0.04% (7/16488) and 1 homozygote. This frequency exceeds the maximal expected allele frequency for a pathogenic SCN5A variant (0.002%; 1/48000) by 20-fold, suggesting this is likely a benign polymorphism in South Asians. This variant was reported in a LQTS patient, however, co-occurrence and co-segregation information was not specified and therefore, the causative correlation cannot be established. The variant was also found in one colorectal tumor as a somatic variant. The variant of interest has not, to our knowledge, been evaluated for functional impact by in vivo/vitro studies. However, multiple clinical laboratories and databases classified this variant as pathogenic or VUS. Considering all available data, this variant is classified as a VUS-possibly benign variant.
Invitae RCV000459958 SCV000545056 uncertain significance Brugada syndrome 2017-11-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 579 of the SCN5A protein (p.Gly579Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs199473128, ExAC 0.04%). This variant has been reported in an individual with long QT syndrome (PMID: 16414944) and it has also been reported in an unaffected individual (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 67686). This variant identified in the SCN5A gene is located in the interdomain linker DI/DII region of the resulting protein (PMID: 25348405), but 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 C25"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454856 SCV000540283 uncertain significance not specified 2016-08-11 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported as a novel longQT variant in 2005 - proband count not provided. Also reported in 1 ostensibly healthy adult. ClinVar: P by GeneDx

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