ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.7180G>C (p.Asp2394His) (rs1554401561)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000649103 SCV000770928 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 2394 of the FLNC protein (p.Asp2394His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLNC-related disease. 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: "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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853258 SCV000996084 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-11-29 criteria provided, single submitter clinical testing This variant has not been previously reported in the literature to our knowledge and it is absent from the ExAC and gnomAD population databases, thus it is presumed to be rare. This variant is a non-conservative amino acid change in a missense intolerant gene. The residue is highly conserved among eukaryotes and the change is predicted to be damaging by in silico methods. No functional characterizations of the variant are available for review but missense variants in this gene have previously been demonstrated to cause disease (PMID: 26666891, 25351925). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.7180G>C, p.Asp2394His variant is classified as likely pathogenic.

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