ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.296C>G (p.Pro99Arg) (rs370435862)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764970 SCV000896147 uncertain significance Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000182257 SCV000234560 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNQ1 gene. The P99R variant has previously been reported in one case of sudden unexplained death, a 2 month-old female who died while sleeping (Wang et al., 2014). This variant has also been identified independently of additional cardiogenetic variants in two other individuals referred for arrythmia genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The P99R variant is observed in 2/13408 (0.01%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The P99R 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000801967 SCV000941773 uncertain significance Long QT syndrome 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 99 of the KCNQ1 protein (p.Pro99Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs370435862, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual who suffered sudden unexplained death (PMID: 24631775). ClinVar contains an entry for this variant (Variation ID: 200877). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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