rs387906587
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_001458.5(FLNC):c.577G>A(p.Ala193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A193A) has been classified as Likely benign.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.577G>A | p.Ala193Thr | missense_variant | 2/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.577G>A | p.Ala193Thr | missense_variant | 2/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.577G>A | p.Ala193Thr | missense_variant | 2/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.577G>A | p.Ala193Thr | missense_variant | 2/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 11, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2018 | The A193T variant in the FLNC gene has previously been reported to segregate with disease in at least one family with distal myopathy (Duff et al., 2011). Functional studies show that A193T increases the actin-binding activity of the filamin C protein compared to wild-type (Duff et al., 2011). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A193T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. The A193T variant is a strong candidate for a pathogenic variant. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Myofibrillar myopathy 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Jan 29, 2024 | The FLNC c.577G>A (p.Ala193Thr) variant has been observed in at least nine individuals with FLNC-related myopathy including at least one individual with scoliosis and segregates with first degree relatives in 3 families (Duff RM et al., PMID: 21620354; Previtali SC et al., PMID: 30734317; Töpf A et al., PMID: 32528171; van den Bogaart FJ et al., PMID: 27816332). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by six submitters and a variant of uncertain significance by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in the actin binding domain and computational predictors indicate that the variant is damaging, evidence that correlates with impact to FLNC function. In support of this prediction, functional studies show that the variant increases the actin-binding activity of the filamin C protein compared to wild-type and results in protein aggregates when transfected (Duff RM et al., PMID: 21620354). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
Distal myopathy with posterior leg and anterior hand involvement Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 10, 2011 | - - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2022 | ClinVar contains an entry for this variant (Variation ID: 29592). This missense change has been observed in individuals with FLNC-related myopathy (PMID: 2781633, 21620354, 30734317). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 193 of the FLNC protein (p.Ala193Thr). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FLNC function (PMID: 21620354). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 18, 2016 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala193Thr variant in FLNC has been reported in 1 individual with distal myopathy and segr egated with disease in 2 affected relatives (Duff 2011). This variant was absent from large population studies. In vitro functional studies provide some evidenc e that the p.Ala193Thr variant may impact protein function (Duff 2011). However, these types of assays may not accurately represent biological function. Computa tional prediction tools and conservation analysis suggest that the p.Ala193Thr v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a path ogenic role, the clinical significance of the p.Ala193Thr variant is uncertain. - |
Desmin-related myofibrillar myopathy;C1836050:Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 05-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at