chr7-128856894-GGTCCTGGGCTCGA-G

Variant names:

• chr7-128856894-GGTCCTGGGCTCGA-G
• rs1554401837
• NM_001458.5:c.7536_7548delTCCTGGGCTCGAG

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.7536_7548delTCCTGGGCTCGAG​(p.Pro2513GlufsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 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 7-128856894-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 rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.7536_7548delTCCTGGGCTCGAG	p.Pro2513GlufsTer12	frameshift_variant	Exon 45 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.7437_7449delTCCTGGGCTCGAG	p.Pro2480GlufsTer12	frameshift_variant	Exon 44 of 47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.103-3510_103-3498delTCGAGCCCAGGAC		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.7536_7548delTCCTGGGCTCGAG	p.Pro2513GlufsTer12	frameshift_variant	Exon 45 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.7437_7449delTCCTGGGCTCGAG	p.Pro2480GlufsTer12	frameshift_variant	Exon 44 of 47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.103-3510_103-3498delTCGAGCCCAGGAC		intron_variant	Intron 1 of 3	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

Jan 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;