rs387906587

Positions:

• chr7-128835550-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

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: Genomes: not found (cov: 32)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1 O:1
• Conservation: PhyloP100: 10.0

Genes affected

FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNC
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 7-128835550-G-A is Pathogenic according to our data. Variant chr7-128835550-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 29592.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}. Variant chr7-128835550-G-A is described in Lovd as [Likely_pathogenic].

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

Alfa AF: 0.00211 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.75		Loss of stability (P = 0.0711);Loss of stability (P = 0.0711);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906587; hg19: chr7-128475604; COSMIC: COSV57967712;