rs1371853934

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001458.5(FLNC):​c.1589A>T​(p.Asp530Val) variant causes a missense change. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

FLNC
NM_001458.5 missense

Scores

11
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.48
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.1589A>T p.Asp530Val missense_variant Exon 10 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.1589A>T p.Asp530Val missense_variant Exon 10 of 47 NP_001120959.1 Q14315-2Q59H94

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.1589A>T p.Asp530Val missense_variant Exon 10 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1
FLNCENST00000346177.6 linkc.1589A>T p.Asp530Val missense_variant Exon 10 of 47 1 ENSP00000344002.6 Q14315-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.000447
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Uncertain:1
Jul 23, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces aspartic acid with valine at codon 530 of the FLNC protein (p.Asp530Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLNC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;.
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
H;H
PrimateAI
Benign
0.39
T
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.014
D;D
Polyphen
0.96
D;D
Vest4
0.68
MutPred
0.79
Gain of catalytic residue at D530 (P = 0.0315);Gain of catalytic residue at D530 (P = 0.0315);
MVP
0.88
MPC
0.56
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.66
gMVP
0.68

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1371853934; hg19: chr7-128480641; API