rs786205178

Positions:

• chrX-154352311-GCTGA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001110556.2(FLNA):​c.6635_6638del​(p.Val2212AlafsTer2) variant causes a frameshift 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 25)
• Consequence: FLNA NM_001110556.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.22

Genes affected

FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154352311-GCTGA-G is Pathogenic according to our data. Variant chrX-154352311-GCTGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 190179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154352311-GCTGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.6635_6638del	p.Val2212AlafsTer2	frameshift_variant	41/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.6611_6614del	p.Val2204AlafsTer2	frameshift_variant	40/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.6635_6638del	p.Val2212AlafsTer2	frameshift_variant	41/48	1	NM_001110556.2	ENSP00000358866

Frequencies

GnomAD3 genomes Cov.: 25

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

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FLNA: PVS1, PM2, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2015	The c.6611_6614delTCAG ( or c.6635delTCAG due to use of alternate transcript) mutation in the FLNA gene has previously been reported in association with FLNA-disorder in a 42-year-old female with ventricular septal defects and aortic regurgitation, surgically corrected ventricular septal defect, bilateral PH and enlarged retrocerebellar space (de Wit MC et al., 2011). This individuals family history revealed her mother died of rupture of aorta, sibling with mild aortic regurgitation, and the patient had a healthy son (De Wit et al., 2011). This mutation causes a shift in reading frame starting at codon Valine 2204, changing it to an Alanine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Val2204AlafsX2. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the FLNA gene have been reported in association with FLNA-related disorder. Furthermore, the c.6611_6614delTCAG mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.6611_6614delTCAG in the FLNA gene is interpreted as a disease-causing mutation. -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 190179). This premature translational stop signal has been observed in individual(s) with periventricular heterotopia (PMID: 20730588). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val2204Alafs*2) in the FLNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLNA are known to be pathogenic (PMID: 16684786, 20730588, 26471271). -

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Claritas Genomics

Oct 27, 2010

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786205178; hg19: chrX-153580679;