Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000530031 | SCV000651177 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2022-12-02 | criteria provided, single submitter | clinical testing | 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. 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"). ClinVar contains an entry for this variant (Variation ID: 472182). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2612 of the FLNC protein (p.Glu2612Lys). |
Ambry Genetics | RCV004024201 | SCV005017805 | uncertain significance | Cardiovascular phenotype | 2023-10-12 | criteria provided, single submitter | clinical testing | The p.E2612K variant (also known as c.7834G>A), located in coding exon 47 of the FLNC gene, results from a G to A substitution at nucleotide position 7834. The glutamic acid at codon 2612 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Stanford Center for Inherited Cardiovascular Disease, |
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. |