rs1420159591

chr7-128840055-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001458.5(FLNC):c.1444C>T(p.Arg482Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FLNC NM_001458.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.695

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-128840055-C-T is Pathogenic according to our data. Variant chr7-128840055-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517207.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}. Variant chr7-128840055-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.1444C>T	p.Arg482Ter	stop_gained	9/48	ENST00000325888.13
FLNC	NM_001127487.2	c.1444C>T	p.Arg482Ter	stop_gained	9/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.1444C>T	p.Arg482Ter	stop_gained	9/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.1444C>T	p.Arg482Ter	stop_gained	9/47	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 04, 2022

- -

Hypertrophic cardiomyopathy 26 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is the established mechanism of disease for variants in dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047), myofibrillar myopathy (MIM#609524) and arrhythmogenic right ventricular cardiomyopathy. In distal myopathy (MIM#614065), NMD-predicted variants cause a loss of function, however missense variants have been shown to result in a toxic gain of function (PMID: 32112656). (I) 0107 - This gene is associated with autosomal dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and mostly observed in individuals with dilated cardiomyopathy (DCM) (DECIPHER, PMID: 32112656). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, however more recently it has been classified as pathogenic in at least five unrelated individuals with arrhythmogenic cardiomyopathy (ARVC) or DCM (ClinVar - personal communication, PMID: 31627847 (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate in two families with DCM or ARVC (PMID: 29235529, PMID: 31627847). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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 22, 2023

This sequence change creates a premature translational stop signal (p.Arg482*) in the FLNC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 29235529). ClinVar contains an entry for this variant (Variation ID: 517207). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg482X v ariant in FLNC has not been previously reported in individuals with cardiomyopat hy but has been identified by our laboratory in 1 individual with DCM and segreg ated with disease in at least 1 affected relative. It was absent from large popu lation studies. This nonsense variant leads to a premature termination codon at position 482, which is predicted to lead to a truncated or absent protein. The F LNC gene is associated with myofibrillar myopathy but variants have recently als o been reported in individuals with isolated inherited cardiomyopathies (includi ng HCM, DCM and RCM). Overall the number of reported variants is still low and l oss of function as a disease mechanism is not yet firmly established for this ge ne. In summary, while there is some suspicion for a pathogenic role, the clinica l significance of the p.Arg482X variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.52	D
MutationTaster	Benign	1.0	A;A
Vest4		0.84
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs1420159591; hg19: chr7-128480109;