7-128848926-C-T

Variant names:

• chr7-128848926-C-T
• rs879255639
• NM_001458.5:c.4871C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

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 Likely pathogenic (★★). 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.08
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 253126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.4871C>T	p.Ser1624Leu	missense_variant	Exon 28 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.4871C>T	p.Ser1624Leu	missense_variant	Exon 28 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.4871C>T	p.Ser1624Leu	missense_variant	Exon 28 of 48	1	NM_001458.5	ENSP00000327145.8

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 26 Pathogenic:2

Jun 26, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 10, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Cardiomyopathy Pathogenic:1

Oct 14, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FLNC-related disorder Pathogenic:1

Feb 18, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 26, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

Jan 13, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 identified in one or more individuals with features consistent with FLNC-related hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy and segregated with disease in at least one family (Brodehl A et al. Hum. Mutat., 2016 Mar;37:269-79; Ader F et al. Clin. Genet., 2019 10;96:317-329; Hagège A et al. Int J Cardiol. 2024 Dec;417:132542; Ambry internal data). Based on internal structural analysis, this variant is predicted to be mildly disruptive (Brodehl A et al. Hum. Mutat., 2016 Mar;37:269-79; 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic for FLNC-related hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy; however, its clinical significance for FLNC-related dilated cardiomyopathy is uncertain. -

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

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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
PhyloP100		6.1
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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255639; hg19: chr7-128488980; COSMIC: COSV100369004; COSMIC: COSV100369004;