rs1554401837

chr7-128856894-GGTCCTGGGCTCGA-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001458.5(FLNC):c.7536_7548del(p.Pro2513GlufsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.97

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-128856894-GGTCCTGGGCTCGA-G is Pathogenic according to our data. Variant chr7-128856894-GGTCCTGGGCTCGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 539437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128856894-GGTCCTGGGCTCGA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.7536_7548del	p.Pro2513GlufsTer12	frameshift_variant	45/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.103-3510_103-3498del		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.7437_7449del	p.Pro2480GlufsTer12	frameshift_variant	44/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.7536_7548del	p.Pro2513GlufsTer12	frameshift_variant	45/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.7437_7449del	p.Pro2480GlufsTer12	frameshift_variant	44/47	1		A1
FLNC-AS1	ENST00000469965.1	n.103-3510_103-3498del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.7536_7548del13 pathogenic mutation, located in coding exon 45 of the FLNC gene, results from a deletion of 13 nucleotides at nucleotide positions 7536 to 7548, causing a translational frameshift with a predicted alternate stop codon (p.P2513Efs*12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is expected to be causative of FLNC-related dilated cardiomyopathy; however, its clinical significance for FLNC-related hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy is unclear. -

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

Jan 29, 2024

This sequence change creates a premature translational stop signal (p.Pro2513Glufs*12) 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 arrhythmia (PMID: 30118858). ClinVar contains an entry for this variant (Variation ID: 539437). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554401837; hg19: chr7-128496948;