rs28935473

Variant names:

• chrX-154360199-G-A
• rs28935473
• NM_001110556.2:c.3596C>T

Variant summary

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

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.3596C>T	p.Ser1199Leu	missense_variant	Exon 22 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.3596C>T	p.Ser1199Leu	missense_variant	Exon 22 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.3596C>T	p.Ser1199Leu	missense_variant	Exon 22 of 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

Nov 02, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Dec 17, 2008

Claritas Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1199 of the FLNA protein (p.Ser1199Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Melnick Needles syndrome (PMID: 12612583, 20186808, 26404489). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11759). 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 FLNA protein function. For these reasons, this variant has been classified as Pathogenic. -

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;