rs28935469

Variant names:

• chrX-154367844-G-A
• rs28935469
• NM_001110556.2:c.620C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154367844-G-A
• chrX-154367844-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 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 (★★).

• 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:10
• 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 16 ACMG points.

• PM1: In a domain Calponin-homology (CH) 2 (size 103) in uniprot entity FLNA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001110556.2
• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.620C>T	p.Pro207Leu	missense_variant, splice_region_variant	Exon 3 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.620C>T	p.Pro207Leu	missense_variant, splice_region_variant	Exon 3 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.620C>T	p.Pro207Leu	missense_variant, splice_region_variant	Exon 3 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oto-palato-digital syndrome, type I Pathogenic:3

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 10, 2024

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_v1.3.5, 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 otopalatodigital 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 proline to leucine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple unrelated hemizygous males with otopalatodigital syndrome, and mildly affected heterozygous females (PMID: 31942422, 27193221). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) -

Jan 16, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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

Oct 21, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Pathogenic:1

Nov 20, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jan 24, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 11755). 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"). For these reasons, this variant has been classified as Pathogenic. -

FLNA-related disorder Pathogenic:1

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
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;