rs1131692185

Positions:

• chr7-128845012-GC-CT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_001458.5(FLNC):​c.3547_3548delGCinsCT​(p.Ala1183Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-128845012-GC-CT is Pathogenic according to our data. Variant chr7-128845012-GC-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430733.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.3547_3548delGCinsCT	p.Ala1183Leu	missense_variant		ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.3547_3548delGCinsCT	p.Ala1183Leu	missense_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.3547_3548delGCinsCT	p.Ala1183Leu	missense_variant		1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.3547_3548delGCinsCT	p.Ala1183Leu	missense_variant		1		ENSP00000344002.6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 26 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

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

Jun 12, 2017

The variant is absent in both parents so presumably suggested to be de novo even though the paternity verification was not performed. The patient presented with severe restrictive cardiomyopathy with moderate myocardial hypertrophy during the first year of life accompanied by mild limb girdle and proximal muscle weakness. No severe arrhythmias or signs and of central nervous system involvement are detected. The patient was listed to heart transplantation list at the age of 3 due to progressive heart failure. The two nucleotide change in FLNC resulted in A1183L predicted to be deleterious by prediction analysis. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131692185; hg19: chr7-128485066;