Submissions for variant NM_001458.5(FLNC):c.577G>A (p.Ala193Thr)

dbSNP: rs387906587

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442836	SCV000521263	likely pathogenic	not provided	2018-07-31	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000600715	SCV000712399	uncertain significance	not specified	2016-08-18	criteria provided, single submitter	clinical testing	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.
Invitae	RCV001384941	SCV001584637	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2022-12-17	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000442836	SCV002023741	pathogenic	not provided	2020-02-11	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555848	SCV005045159	pathogenic	Myofibrillar myopathy 5	2024-01-29	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000022429	SCV000043718	pathogenic	Distal myopathy with posterior leg and anterior hand involvement	2011-06-10	no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV001535684	SCV001749758	not provided	Myofibrillar myopathy 5; Desmin-related myofibrillar myopathy; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26		no assertion provided	phenotyping only	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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000442836	SCV001808738	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000442836	SCV001951888	likely pathogenic	not provided		no assertion criteria provided	clinical testing