7-128848616-G-A

Position:

• chr7-128848616-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001458.5(FLNC):​c.4636G>A​(p.Gly1546Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 8.15

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 7-128848616-G-A is Pathogenic according to our data. Variant chr7-128848616-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472074.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.4636G>A	p.Gly1546Ser	missense_variant	27/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.4636G>A	p.Gly1546Ser	missense_variant	27/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.4636G>A	p.Gly1546Ser	missense_variant	27/48	1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.4636G>A	p.Gly1546Ser	missense_variant	27/47	1		ENSP00000344002	A1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249032 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 26 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.4636G>A(p.Gly1546Ser) variant in FLNC gene has been reported previously in heterozygous state in individual(s) affected with cardiomyopathies (Verdonschot et al., 2020). This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Gly at position 1546 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly1546Ser in FLNC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. The missense variants in the ROD2 domain are enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is the established mechanism of disease for variants in dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047) and myofibrillar myopathy (MIM#609524). In distal myopathy (MIM#614065), NMD-predicted variants cause a loss of function; however missense variants have been shown to result in a toxic gain of function (PMID: 32112656). (I) 0107 - This gene is associated with autosomal dominant disease. Variants located throughout the gene that are predicted to result in nonsense-mediated decay (NMD) are enriched in dilated cardiomyopathy, whereas missense variants in the ROD2 domain are enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy (MIM#617047). Additionally, myofibrillar myopathy (MIM#609524) is known to result from either missense variants in the ROD2 domain or truncating variants in the Ig-like domain 24, while missense variants in the actin-binding domain and NMD-predicted variants located in the Ig-like domain 15 and have been reported for distal myopathy (MIM#614065) (PMID: 32112656). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Gly1546Asp):1 heterozygote, 0 homozygotes). (I) 0600 - Variant is located in the annotated Ig-like ROD1 domain (PMID: 32112656). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity. This variant has been described in one large multi-generational family with restrictive cardiomyopathy (Sanoja, A.J. et al. 2018). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with sixteen affected individuals in one multi-generational family with restrictive cardiomyopathy. Non-segregation of the variant with disease was not demonstrated (Sanoja, A.J. et al. 2018). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by parental segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 25, 2017	Found in a Caucasian teenager with a new diagnosis of HCM and a long history of prolonged QTc intervals. He had a 130-gene Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. Results included 4 variants: -p.Arg187Leu (c.560G>T) in the DOLK gene -p.Leu691Phe (c.2071C>T) in the DSP gene -p.Gly1546Ser (c.4636G>A) in the FLNC gene -p.Arg216Gln (c.647G>A) in the JUP gene p.Gly1546Ser (c.4636G>A) in exon 27 of the FLNC gene (NM_001458.4) Chromosome location 7:128488670 G / A Invitae classifies this as a Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. However, we consider it a good candidate for a disease-causing variant. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. The FLNC (filamin C) gene is associated with autosomal dominant myofibrillar myopathy 5 (MFM5) (MedGen UID: 372186), distal myopathy 4 (MPD4) (MedGen UID: 481352), dilated cardiomyopathy (PMID: 25633252, 27908349), and hypertrophic cardiomyopathy (PMID: 25351925, 28356264). Additionally, the FLNC gene has preliminary evidence supporting a correlation with autosomal dominant restrictive cardiomyopathy (PMID: 26666891). Of the variants in FLNC that are currently listed in ClinVar as Likely Pathogenic or Pathogenic, approximately half are missense and half are truncating, loss-of-function variants. This is a nonconservative missense amino acid change, resulting in the replacement of a nonpolar Glycine with a polar Serine. Glycine at this location is highly conserved across ~100 vertebrate species for which we have data. The adjacent residues are also highly conserved. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side. However, Valdes-Mas et al (2014) and, from the same group, Gomez et al (2017) reported a nearby variant, p.Ala1539Thr, as causing HCM in two separate Spanish families. They classified it as Likely Pathogenic. It segregated with HCM across 7 family members in one family, and 4 in another. Various affected family members had atrial fibrillation, heart failure, and/or transplant. Cardiac muscle histology from the 1 family member who underwent heart transplantation showed marked sarcomeric abnormalities, including myofibrillar disarray, sarcomeric aggregates, and fibrosis; immunohistochemical staining confirmed the presence of filamin C in the sarcomeric aggregates. In contrast, skeletal muscle biopsy from an affected individual showed intact sarcomeric structures and normal ATPase, SDH, and NADH staining, as well as the absence of the characteristic small aggregates of myofibrillar myopathy. Our patient's variant, Gly1546Ser, was reported in 3 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 3 non-Finnish European individuals (for the highest allele frequency: 0.002%), with overall MAF in gnomAD 0.001%. Another variant at the same codon, Gly1546Asp, was reported in 1 non-Finnish European individual. There is good coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32112656, 36252119) -

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1546 of the FLNC protein (p.Gly1546Ser). This variant is present in population databases (rs774263134, gnomAD 0.002%). This missense change has been observed in individual(s) with restrictive cardiomyopathy (PMID: 32112656; Sanoja et al. 2018. J Transl Genet Genom. 2:6). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 472074). 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	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.069	T;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.74		Gain of glycosylation at G1546 (P = 0.0197);Gain of glycosylation at G1546 (P = 0.0197);
MVP		0.86
MPC		0.96
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.73

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: rs774263134; hg19: chr7-128488670;