X-154348850-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_001110556.2(FLNA):c.7941_7942del(p.Ter2648SerfsTer101) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P2647P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 frameshift, stop_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.22

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2648 codons.
• PP5: Variant X-154348850-CAG-C is Pathogenic according to our data. Variant chrX-154348850-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 213498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154348850-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.7941_7942del	p.Ter2648SerfsTer101	frameshift_variant, stop_lost	48/48	ENST00000369850.10
FLNA	NM_001456.4	c.7917_7918del	p.Ter2640SerfsTer101	frameshift_variant, stop_lost	47/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.7941_7942del	p.Ter2648SerfsTer101	frameshift_variant, stop_lost	48/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 24

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

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Invitae

Sep 17, 2023

This protein extension has been observed in individual(s) with bilateral periventricular heterotopia, congenital short bowel, and additional FLNA-related conditions (PMID: 23873601, 28428218). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this protein extension alters FLNA gene expression (PMID: 23873601, 28428218). ClinVar contains an entry for this variant (Variation ID: 213498). This variant is also known as c.7941_7942delCT (p.2648Serext*100). This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the FLNA mRNA. It is expected to extend the length of the FLNA protein by 100 additional amino acid residues. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2015

The c.7917_7918delCT mutation has been reported previously (using alternative nomenclature c.7941_7942delCT) in association with a form of X-linked periventricular nodular heterotopia (XL-PNH) in a family consisting of 2 brothers, their mother, a maternal aunt and her son, another maternal aunt and the maternal grandmother (Oegema et al., 2013). The phenotype of the brothers and male first cousin was characterized by failure to thrive, distinct facial appearance, and variable multi-organ involvement, including PNH, congenital short bowel with malrotation, wandering spleen, cardiovascular and urinary tract abnormalities (Oegema et al., 2013). Diminished FLNA protein levels were observed in the 2 affected brothers as compared to their mother, who was reported to be healthy although she carried the c.7917_7918delCT mutation (Oegema et al., 2013). Additionally, expression of mRNA was down-regulated in both brothers and their mother (Oegema et al., 2013). The other female family members carrying the mutation (maternal aunt and grandmother) demonstrated additional phenotypic variability including PNH, seizures, mitral valve prolapse, umbilical hernia, joint pain, hypertelorism, depression, anxiety, and/or a history of miscarriages (Oegema et al., 2013). This deletion destroys the natural stop codon at position 2640, replaces it with a Serine residue and extends the protein by 100 amino acids, denoted p.X2640SextX100. This mutation was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, c.7917_7918delCT is considered a pathogenic mutation. -

Heterotopia, periventricular, X-linked dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs863223636; hg19: chrX-153577218;