7-128846396-C-T

Position:

• chr7-128846396-C-T

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.4060C>T​(p.Arg1354Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,232 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FLNC NM_001458.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.402

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 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 7-128846396-C-T is Pathogenic according to our data. Variant chr7-128846396-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 70588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846396-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.4060C>T	p.Arg1354Ter	stop_gained	23/48	ENST00000325888.13
FLNC	NM_001127487.2	c.4060C>T	p.Arg1354Ter	stop_gained	23/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.4060C>T	p.Arg1354Ter	stop_gained	23/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.4060C>T	p.Arg1354Ter	stop_gained	23/47	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458232 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725610

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32112656, 28436997) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2021

The p.R1354* pathogenic mutation (also known as c.4060C>T), located in coding exon 23 of the FLNC gene, results from a C to T substitution at nucleotide position 4060. This changes the amino acid from an arginine to a stop codon within coding exon 23. This mutation was reported in an individual with familial dilated cardiomyopathy (Janin A et al. Clin Genet, 2017 Dec;92:616-623). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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

Aug 07, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 28436997). ClinVar contains an entry for this variant (Variation ID: 70588). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1354*) in the FLNC gene. It is expected to result in an absent or disrupted protein product. -

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	Benign	-0.073
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.64	D
MutationTaster	Benign	1.0	A;A
Vest4		0.90
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Other links and lift over

dbSNP: rs138193236; hg19: chr7-128486450; COSMIC: COSV57951912; COSMIC: COSV57951912;