ClinVar Miner

Submissions for variant NM_001110556.2(FLNA):c.7927C>T (p.Arg2643Cys) (rs200836471)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197706 SCV000250431 uncertain significance not provided 2015-02-10 criteria provided, single submitter clinical testing The R2635C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R2635C variant was not observed with any significant frequency in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and reported in 1/692 (0.14%) hemizygous male of Hispanic ancestry in the 1000 Genomes Project. The R2635C 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. This substitution occurs at a position that is conserved across mammalian species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no definitive missense mutations in nearby residues have been reported in association with periventricular heterotopia. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-1
Invitae RCV000525068 SCV000639840 uncertain significance Periventricular nodular heterotopia 1; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 1 2017-04-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2635 of the FLNA protein (p.Arg2635Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200836471, ExAC 0.01%) but has not been reported in the literature in individuals with a FLNA-related disease. ClinVar contains an entry for this variant (Variation ID: 213511). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on 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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