7-128852854-G-A

Position:

• chr7-128852854-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.6031G>A​(p.Gly2011Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.89

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]

FLNC-AS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 7-128852854-G-A is Pathogenic according to our data. Variant chr7-128852854-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472122.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.6031G>A	p.Gly2011Arg	missense_variant	37/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.5932G>A	p.Gly1978Arg	missense_variant	36/47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.215+431C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.6031G>A	p.Gly2011Arg	missense_variant	37/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.5932G>A	p.Gly1978Arg	missense_variant	36/47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.215+431C>T		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35456187, 34263907, Hernandez2020, 32659924, 34971931) -

Restrictive cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

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- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2011 of the FLNC protein (p.Gly2011Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FLNC-related conditions (PMID: 32659924; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 472122). 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. This variant disrupts the p.Gly2011 amino acid residue in FLNC. Other variant(s) that disrupt this residue have been observed in individuals with FLNC-related conditions (PMID: 30418145), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2024

The p.G2011R variant (also known as c.6031G>A), located in coding exon 37 of the FLNC gene, results from a G to A substitution at nucleotide position 6031. The glycine at codon 2011 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in individuals with restrictive cardiomyopathy (RCM) (Kolokotronis K et al. J Clin Med, 2020 Jul;9:[ePub ahead of print]; Lopes LR et al. Eur Heart J, 2021 Aug;42:3063-3073). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.92		Gain of MoRF binding (P = 0.0081);.;
MVP		0.86
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554400962; hg19: chr7-128492908;