rs28935473

Positions:

• chrX-154360199-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001110556.2(FLNA):​c.3596C>T​(p.Ser1199Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.89

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 13 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), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant X-154360199-G-A is Pathogenic according to our data. Variant chrX-154360199-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360199-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.3596C>T	p.Ser1199Leu	missense_variant	22/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.3596C>T	p.Ser1199Leu	missense_variant	22/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.3596C>T	p.Ser1199Leu	missense_variant	22/48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melnick-Needles syndrome Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Claritas Genomics	Dec 17, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 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 variants are reported to cause periventricular nodular heterotopia, X-linked cardiac valvular dystrophy and gastrointestinal diseases, whereas gain of function missense variants and small in-frame deletions lead to the Oto-palato-digital spectrum of disease. X-linked cardiac valvular dystrophy is caused by mostly missense or splice variants in filamin repeats 1, 4, 5, 6 and 7 (PMID:30089473). (I) 0108 - This gene is associated with both X-linked recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated RD10 domain (PMID: 26404489). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in heterozygous females with Melnick-Needles syndrome and a hemizygous male fetus with otopalatodigital spectrum disorder. In several of these individuals the variant was proven to be de novo (ClinVar, PMID: 12612583, PMID: 26404489). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. However, the variant has been shown to be de novo in a research setting (Broad Institute). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 02, 2022	The FLNA c.3596C>T variant is classified as a LIKELY PATHOGENIC variant (PS4, PM2, PP3) The variant is a single nucleotide change in exon 22/48 of the FLNA gene, which is predicted to change the amino acid serine at position 1199 in the protein to leucine. This is a recurrent pathogenic variant in the FLNA gene, and has been previously reported in many individuals affected with Melnick Needle syndrome in both states of hemizygous (in males, more severe) and heterozygous (in females, less severe) (PMID: 12612583, 20186808 26404489) (PS4). The variant is in dbSNP (rs28935473) but is absent from population databases (PM2). The variant has been reported in ClinVar as pathogenic (Variation ID: 11759). The variant has been reported in HGMD as disease causing (Accession no.: CM030673). Computational predictions support a deleterious effect on the gene or gene product (PP3). Clinical review is recommended. *Hemizygous mutation in males causes more severe phenotypes. Monoallelic mutations in females may cause disease with less severe, later onset than males. **'Limited' Gene-disease association with Vascular abnormality and hyperflexi joint (EDS-like) (PMID: 29334594) (AusPanelApp 2022). -

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

Dec 23, 2016

This variant has been reported in the literature in more than 6 individuals affected with Melnick Needles syndrome, with several of them being reported as de novo events (PMID: 12612583, 20186808, 26404489). ClinVar contains an entry for this variant (Variation ID: 11759). In summary, this variant is a well established pathogenic rare missense change that has been reported in multiple affected individuals. For these reasons, this variant has been classified as Pathogenic. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 1199 of the FLNA protein (p.Ser1199Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.;M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	D;.;D;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0080	D;.;D;D;.
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		1.0	D;.;P;P;.
Vest4		0.85
MutPred		0.61		Loss of disorder (P = 0.0888);.;Loss of disorder (P = 0.0888);Loss of disorder (P = 0.0888);.;
MVP		0.99
MPC		0.55
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.79

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: rs28935473; hg19: chrX-153588567; COSMIC: COSV61040824; COSMIC: COSV61040824;