ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.4636G>A (p.Gly1546Ser) (rs774263134)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543625 SCV000651038 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2017-11-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1546 of the FLNC protein (p.Gly1546Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. While this variant is present in population databases (rs774263134), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University 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.

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