rs1114167361

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001458.5(FLNC):c.3557C>T(p.Ala1186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,446 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.37

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.757

PP5

Variant 7-128845022-C-T is Pathogenic according to our data. Variant chr7-128845022-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128845022-C-T is described in Lovd as [Pathogenic]. Variant chr7-128845022-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-128845022-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.3557C>T	p.Ala1186Val	missense_variant	Exon 21 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.3557C>T	p.Ala1186Val	missense_variant	Exon 21 of 47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.3557C>T	p.Ala1186Val	missense_variant	Exon 21 of 48	1	NM_001458.5	ENSP00000327145.8		Q14315-1
FLNC	ENST00000346177.6 link	c.3557C>T	p.Ala1186Val	missense_variant	Exon 21 of 47	1		ENSP00000344002.6		Q14315-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727048

show subpopulations

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 26

Pathogenic:2

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The patient was diagnosed with restrictive cardiomyopathy at the age of 3 diagnosed due to atrial enlargement. Mild signs of myopathy and neuropathy including muscle hypotonia were observed and confirmed by electromyography. The parents refused the genetic screening, and so de novo character of mutation was not confirmed. Similar variant was detected in another patient with restrictive cardiomyopathy at the age of 1.5 yr. From the age of a year patient's mother was worried about hyperhidrosis, tiredness and heavy breathing. There were noted atrium dilation and open foramen ovale. Besides, myocardial contractility is without changes with an additional systolic impulse. He presented with more prominent clinical signs of myopathy and involvement of central nervous system. -

Mar 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

Myofibrillar myopathy 5

Pathogenic:2

Jun 06, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2,PS4,PS3_SUP,PM2_SUP -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Aug 08, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29858533, 32112656, 33060286, 21520333, 32154132, 26436962) -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Sep 18, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the musculature

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1186 of the FLNC protein (p.Ala1186Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital myopathy and/or myofibrillar myopathy (PMID: 21520333, 26436962; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 427928). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.97

D;D

Vest4

0.79

MutPred

0.54

Gain of catalytic residue at A1186 (P = 0.0315);Gain of catalytic residue at A1186 (P = 0.0315);

MVP

0.68

MPC

0.89

ClinPred

0.98

GERP RS

5.6

Varity_R

0.49

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over