7-128848926-C-T

Position:

• chr7-128848926-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001458.5(FLNC):​c.4871C>T​(p.Ser1624Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,500 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1624S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 6.08

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNC
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 7-128848926-C-T is Pathogenic according to our data. Variant chr7-128848926-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253126.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2}. Variant chr7-128848926-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.4871C>T	p.Ser1624Leu	missense_variant	28/48	ENST00000325888.13
FLNC	NM_001127487.2	c.4871C>T	p.Ser1624Leu	missense_variant	28/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.4871C>T	p.Ser1624Leu	missense_variant	28/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.4871C>T	p.Ser1624Leu	missense_variant	28/47	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461500 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727046

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 26 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.4871C>T;p.(Ser1624Leu) missense change has been observed in affected individual(s) (PMID: 26666891; 31245841; 32112656) - PS4_supporting.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26666891) - PS3_supporting. This variant is not present in population databases:rs879255639, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 26666891) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 26, 2023	- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 14, 2021

- -

FLNC-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Feb 18, 2020

This variant has been previously reported as a heterozygous change in four patients from a family with restrictive cardiomyopathy (PMID: 26666891) and as a heterozygous change in a patient with hypertrophic cardiomyopathy (PMID: 30418145, 31245841). Functional studies have demonstrated that this variant results in protein aggregates consistent with disease in the histopathology of an affected patient's heart tissue and in transfected myoblast cell lines (PMID: 26666891). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0032% (1/31362) and thus is presumed to be rare. The c.4871C>T (p.Ser1624Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.4871C>T (p.Ser1624Leu) variant is classified as Likely Pathogenic. -

Cardiomyopathy, familial restrictive, 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 26, 2023

- -

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

Dec 22, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1624 of the FLNC protein (p.Ser1624Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with restrictive cardiomyopathy (PMID: 26666891, 30418145; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253126). 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. Experimental studies have shown that this missense change affects FLNC function (PMID: 26666891). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2023

The p.S1624L variant (also known as c.4871C>T), located in coding exon 28 of the FLNC gene, results from a C to T substitution at nucleotide position 4871. The serine at codon 1624 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported to segregate with restrictive cardiomyopathy in one family (Brodehl A et al. Hum. Mutat., 2016 Mar;37:269-79). It was also identified in two siblings with hypertrophic cardiomyopathy (Ader F et al. Clin. Genet., 2019 10;96:317-329). This variant has been detected in a cardiomyopathy cohort; however, details were limited (Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). Based on internal structural analysis, this variant is predicted to be mildly disruptive (Amby internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.98	D;D
Vest4		0.92
MutPred		0.72		Gain of catalytic residue at S1624 (P = 0.0549);Gain of catalytic residue at S1624 (P = 0.0549);
MVP		0.88
MPC		0.91
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs879255639; hg19: chr7-128488980; COSMIC: COSV100369004; COSMIC: COSV100369004;