rs28935469

chrX-154367844-G-AchrX-154367844-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001110556.2(FLNA):c.620C>T(p.Pro207Leu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P207Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 missense, splice_region
• Scores: Splicing: ADA: 0.9357
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.93

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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001110556.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-154367844-G-A is Pathogenic according to our data. Variant chrX-154367844-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154367844-G-A is described in Lovd as [Pathogenic]. Variant chrX-154367844-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.620C>T	p.Pro207Leu	missense_variant, splice_region_variant	3/48	ENST00000369850.10
FLNA	NM_001456.4	c.620C>T	p.Pro207Leu	missense_variant, splice_region_variant	3/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.620C>T	p.Pro207Leu	missense_variant, splice_region_variant	3/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oto-palato-digital syndrome, type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2003	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 20, 2018

The FLNA c.620C>T; p.Pro207Leu variant (rs28935469) has been described in individuals with otopalatodigital (OPD) syndrome type I (OPD1), and has shown to segregate with disease in males in at least 2 families (Robertson 2003). It contains an entry in ClinVar (Variation ID: 11755) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 207 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. This variant is located in a calponin homology domain portion of the actin-binding domain, and several variants within this region are associated with OPD syndrome type I and type II, indicating that this domain is likely important for protein function (Hidalgo-Bravo 2005, Kondoh 2007, Marino-Enriquez 2007, Robertson 2003, Sankararaman 2013). Based on available information, this variant is considered pathogenic. REFERENCES Hidalgo-Bravo A et al. A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation. Am J Med Genet A. 2005 Jul 15;136(2):190-3. Kondoh T et al. A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype-genotype correlation. J Hum Genet. 2007;52(4):370-3. Marino-Enriquez A et al. Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G>T mutation: clinical, pathological, and molecular findings. Am J Med Genet A. 2007 May 15;143A(10):1120-5. Robertson S et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003 Apr;33(4):487-91. Sankararaman S et al. Otopalatodigital syndrome type 2 in a male infant: A case report with a novel sequence variation. J Pediatr Genet. 2013 Mar;2(1):33-6. -

Conductive hearing impairment;C0349588:Short stature;C2981150:Cleft palate Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 21, 2015

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2018

The p.P207L variant (also known as c.620C>T), located in coding exon 2 of the FLNA gene, results from a C to T substitution at nucleotide position 620. The proline at codon 207 is replaced by leucine, an amino acid with similar properties. This alteration was first reported to segregate with type I otopalatodigital syndrome (OPD1) in two presumably unrelated families (Dudding BA et al. Am. J. Dis. Child., 1967 Feb;113:214-21; Robertson SP et al. Nat. Genet., 2003 Apr;33:487-91). This alteration was later reported in two affected brothers in a third family with OPD1, where it was not detected in the leukocyte DNA obtained from the mother. Two unaffected brothers in this family were not available for testing (Robertson SP et al. Eur. J. Hum. Genet., 2006 May;14:549-54). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Dec 25, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 11755). This missense change has been observed in individuals with otopalatodigital syndrome (PMID: 3265608, 6019437, 12612583, 16538226, 31942422). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 207 of the FLNA protein (p.Pro207Leu). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12612583, 6019437, 34277511, 31942422, 16538226) -

FLNA-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.620C>T;p.(Pro207Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11755; OMIM: 300017.0009; PMID: 12612583; 31942422; 16538226) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (CH domain; PMID: 15917206) - PM1. This variant is not present in population databases (rs28935469, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 12612583; 31942422; 16538226) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
Cadd	Uncertain	25
Dann	Benign	0.89
DEOGEN2	Pathogenic	0.97	D;.;.;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.6	D;.;D;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.97
MutPred		0.93		Loss of glycosylation at S204 (P = 0.0725);.;Loss of glycosylation at S204 (P = 0.0725);Loss of glycosylation at S204 (P = 0.0725);.;
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.010		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: rs28935469; hg19: chrX-153596212; COSMIC: COSV61043496; COSMIC: COSV61043496;