ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.7834G>A (p.Glu2612Lys) (rs1183050599)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000530031 SCV000651177 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2612 of the FLNC protein (p.Glu2612Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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. ClinVar contains an entry for this variant (Variation ID: 472182). 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786136 SCV000924802 uncertain significance not provided 2017-08-16 no assertion criteria provided provider interpretation FLNC Glu2612Lys c.7834G>A, exon 47, NM_001458.4, hg19 chr7-128498115-G-A Pathogenic variants in the FLNC gene have been associated with autosomal dominant myofibrillar myopathy and, distal myopathy, and dilated cardiomyopathy. There is preliminary evidence associating the gene with autosomal hypertrophic cardiomyopathy and restrictive cardiomyopathy. Given the lack of case data we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Testing was performed by Invitae. We have seen it in a person with HCM. The variant has not been reported in association with disease in the literature. Per the lab report, "The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine...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")." The variant was reported online in 3 of 118,901 individuals (MAF:0.001%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 3 of 16.585 individuals of Latino descent (MAF=0.009%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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