7-128840082-G-C

Variant names:

• chr7-128840082-G-C
• rs770264114
• NM_001458.5:c.1471G>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001458.5(FLNC):​c.1471G>C​(p.Val491Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V491M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.60

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000958 (14/1461764) while in subpopulation MID AF= 0.00139 (8/5768). AF 95% confidence interval is 0.00069. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.1471G>C	p.Val491Leu	missense_variant	Exon 9 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.1471G>C	p.Val491Leu	missense_variant	Exon 9 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.1471G>C	p.Val491Leu	missense_variant	Exon 9 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.1471G>C	p.Val491Leu	missense_variant	Exon 9 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461764 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val491Leu variant in FLNC has not been previously reported in individuals with myopathy or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val491Leu variant is uncertain. -

Cardiovascular phenotype Uncertain:1

Dec 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V491L variant (also known as c.1471G>C), located in coding exon 9 of the FLNC gene, results from a G to C substitution at nucleotide position 1471. The valine at codon 491 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Jul 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 491 of the FLNC protein (p.Val491Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 228688). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.048	B;D
Vest4		0.58
MutPred		0.64		Loss of methylation at K492 (P = 0.0565);Loss of methylation at K492 (P = 0.0565);
MVP		0.62
MPC		0.81
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.70

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: rs770264114; hg19: chr7-128480136; COSMIC: COSV57963552; COSMIC: COSV57963552;