Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000543625 | SCV000651038 | pathogenic | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-08-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1546 of the FLNC protein (p.Gly1546Ser). This variant is present in population databases (rs774263134, gnomAD 0.002%). This missense change has been observed in individual(s) with restrictive cardiomyopathy (PMID: 32112656; Sanoja et al. 2018. J Transl Genet Genom. 2:6). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 472074). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV002272284 | SCV002557405 | pathogenic | Hypertrophic cardiomyopathy 26 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is the established mechanism of disease for variants in dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047) and myofibrillar myopathy (MIM#609524). In distal myopathy (MIM#614065), NMD-predicted variants cause a loss of function; however missense variants have been shown to result in a toxic gain of function (PMID: 32112656). (I) 0107 - This gene is associated with autosomal dominant disease. Variants located throughout the gene that are predicted to result in nonsense-mediated decay (NMD) are enriched in dilated cardiomyopathy, whereas missense variants in the ROD2 domain are enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy (MIM#617047). Additionally, myofibrillar myopathy (MIM#609524) is known to result from either missense variants in the ROD2 domain or truncating variants in the Ig-like domain 24, while missense variants in the actin-binding domain and NMD-predicted variants located in the Ig-like domain 15 and have been reported for distal myopathy (MIM#614065) (PMID: 32112656). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Gly1546Asp):1 heterozygote, 0 homozygotes). (I) 0600 - Variant is located in the annotated Ig-like ROD1 domain (PMID: 32112656). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity. This variant has been described in one large multi-generational family with restrictive cardiomyopathy (Sanoja, A.J. et al. 2018). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with sixteen affected individuals in one multi-generational family with restrictive cardiomyopathy. Non-segregation of the variant with disease was not demonstrated (Sanoja, A.J. et al. 2018). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by parental segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Neuberg Centre For Genomic Medicine, |
RCV002272284 | SCV004176454 | likely pathogenic | Hypertrophic cardiomyopathy 26 | 2023-03-01 | criteria provided, single submitter | clinical testing | The missense c.4636G>A(p.Gly1546Ser) variant in FLNC gene has been reported previously in multiple individuals affected with restrictive cardiomyopathy (Sanoja AJ, et. al., 2018). This variant has been observed to segregate with disease in related individuals (Sanoja AJ, et. al., 2018). The p.Gly1546Ser variant has been reported with allele frequency of 0.0004% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic. The amino acid change p.Gly1546Ser in FLNC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1546 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies are required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786137 | SCV000924803 | uncertain significance | not provided | 2017-10-25 | no assertion criteria provided | provider interpretation | Found in a Caucasian teenager with a new diagnosis of HCM and a long history of prolonged QTc intervals. He had a 130-gene Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. Results included 4 variants: -p.Arg187Leu (c.560G>T) in the DOLK gene -p.Leu691Phe (c.2071C>T) in the DSP gene -p.Gly1546Ser (c.4636G>A) in the FLNC gene -p.Arg216Gln (c.647G>A) in the JUP gene p.Gly1546Ser (c.4636G>A) in exon 27 of the FLNC gene (NM_001458.4) Chromosome location 7:128488670 G / A Invitae classifies this as a Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. However, we consider it a good candidate for a disease-causing variant. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. The FLNC (filamin C) gene is associated with autosomal dominant myofibrillar myopathy 5 (MFM5) (MedGen UID: 372186), distal myopathy 4 (MPD4) (MedGen UID: 481352), dilated cardiomyopathy (PMID: 25633252, 27908349), and hypertrophic cardiomyopathy (PMID: 25351925, 28356264). Additionally, the FLNC gene has preliminary evidence supporting a correlation with autosomal dominant restrictive cardiomyopathy (PMID: 26666891). Of the variants in FLNC that are currently listed in ClinVar as Likely Pathogenic or Pathogenic, approximately half are missense and half are truncating, loss-of-function variants. This is a nonconservative missense amino acid change, resulting in the replacement of a nonpolar Glycine with a polar Serine. Glycine at this location is highly conserved across ~100 vertebrate species for which we have data. The adjacent residues are also highly conserved. According to the Invitae report, 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side. However, Valdes-Mas et al (2014) and, from the same group, Gomez et al (2017) reported a nearby variant, p.Ala1539Thr, as causing HCM in two separate Spanish families. They classified it as Likely Pathogenic. It segregated with HCM across 7 family members in one family, and 4 in another. Various affected family members had atrial fibrillation, heart failure, and/or transplant. Cardiac muscle histology from the 1 family member who underwent heart transplantation showed marked sarcomeric abnormalities, including myofibrillar disarray, sarcomeric aggregates, and fibrosis; immunohistochemical staining confirmed the presence of filamin C in the sarcomeric aggregates. In contrast, skeletal muscle biopsy from an affected individual showed intact sarcomeric structures and normal ATPase, SDH, and NADH staining, as well as the absence of the characteristic small aggregates of myofibrillar myopathy. Our patient's variant, Gly1546Ser, was reported in 3 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 3 non-Finnish European individuals (for the highest allele frequency: 0.002%), with overall MAF in gnomAD 0.001%. Another variant at the same codon, Gly1546Asp, was reported in 1 non-Finnish European individual. There is good coverage at this site. 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. The curators made an effort to exclude individuals with severe pediatric diseases. |