rs1554402015

Variant names:

• chr7-128858155-CT-C
• rs1554402015
• NM_001458.5:c.7929delT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001458.5(FLNC):​c.7929delT​(p.Leu2645CysfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLNC NM_001458.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -6.71

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:53474): (FLNC antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 18 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 7-128858155-CT-C is Pathogenic according to our data. Variant chr7-128858155-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 539430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.7929delT	p.Leu2645CysfsTer23	frameshift_variant	Exon 47 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.7830delT	p.Leu2612CysfsTer23	frameshift_variant	Exon 46 of 47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.102+4369delA		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.7929delT	p.Leu2645CysfsTer23	frameshift_variant	Exon 47 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.7830delT	p.Leu2612CysfsTer23	frameshift_variant	Exon 46 of 47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.102+4369delA		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNC: PVS1:Strong, PM2, PS4:Moderate -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Pathogenic:1

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with FLNC-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FLNC protein in which other variant(s) (p.Trp2710*) have been determined to be pathogenic (PMID: 15929027, 22961544, 26472074, 26969713). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 539430). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu2645Cysfs*23) in the FLNC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acid(s) of the FLNC protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1554402015; hg19: chr7-128498209;