Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FLNA : Familial thoracic aortic aneurysm and aortic dissection

HGNC:3754 | OrphaNet: 91387 | OMIM:300017
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Reinstein E et al. 2013 May (PMID:23032111); (Case M3 = 2 month old male de novo c.5498_5504delCACCCACinsAC indel Cyanotic post-natally; marked dilatation of whole length of aorta, pulmonary arteries (PAs), Ventricular Septal Defect, Atrial Septal Defect, Patent Ductus Arteriosus. Also post-mortem showed intestinal malrotation. Intractable pulmonary hypertension; died sepsis. Not scored - syndromic - other presenting features Case F3= 6 yo female Referred for murmur; gross dilatation of PA + also aorta + head and neck branches p.Tyr731X variant; family study showed this was de novo. Brain MRI shows PNH. Not scored - other presenting features )
Proband with predicted or proven null variant 1.5 0-2 10 1.0 1
Reinstein E et al. 2013 May (PMID:23032111); Ziganshin BA et al. 2015 Nov (PMID:26188975); (PMID 23032111 Case 1 = 38 yo female; SoV aneurysm. Daughter has R subclavian aneurysm; no aortic involvement Periventricular Nodular Heterotopia on brain MRI; no seizures Nonsense mutation in FLNA - p.Asn296Glu fs*38; immunohistochemistry showed 2 fibroblast populations, one of which had no FLNA expression. 0.5pt nonsense mutation with evidence of functional effect Case F5 = 23 y/o female Progressive aortic root dilatation at age 7 (Ix for peripheral cyanosis) + dilated PA Seizures in teens; PNH on brain scan. Joint laxity with recurrent hip subluxations. Nonsense variant: c.7813delC (p.Leu2605fs) Not scored (other presenting features) PMID 26188975: Tested 102 patients by WES; reporting of panel of TAA genes. 1 pt found to have nonsense mutation in FLNA (Y1324X). Family pedigree not reported – no segregation information. Not in ExAC (synonymous variant at same location) 0.5 pt (Due to high pLI score for FLNA, scored 0.5 pt for this proband despite limited info) PMID 15668422: F2 = 16 y/o F with TAA and EDS – like joint laxity /skin features. Variant = c. 4147 del G TAA major feature; no neurology. No segregation. 0.5 pt)
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 0.0 0
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 0.0 0
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 0.0
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 0.0 0
2 4
1.5 3
1 1.5
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 0.0
Aggregate Variant Analysis 0-6 12 0.0
Total Genetic Evidence Points (Maximum 12) 1
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 2.0 2
Pilop C et al. 2009 Sep 15 (PMID:19720936); Subramanian V et al. 2013 (PMID:23977256); (Biochemical Function: PMID 19720936: Role in aortic wall integrity. Increased levels of C terminal fragments of FLNA in dilated aortic walls from BAV and MFS patients. Protein Interactions: PMID 23977256: interaction with angiotensin II: increased C terminal fragmentation with ANgII infusion)
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 0.0
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 3.0 3
Feng Y et al. 2006 Dec 26 (PMID:17172441); Retailleau K et al. 2016 Mar 8 (PMID:26923587); Retailleau K et al. 2016 Jul (PMID:27023351); (PMID 26923587: Mouse with smooth muscle-specific deletion of FLNA at adult stage. Loss of myogenic tone in caudal artery; impaired stretch activation of calcium influx was blunted in the absence of smFlnA: loss of pressure-depndent regulation of arterial tone. PMID 17172441: conditional knockout at adult stage in smooth muscle causes hypertrophic remodeling and increased aortic diameter. PMID 27023351: smooth muscle-specific knockout: hemizygous males die by E14.5 from vascular rupture and fragility.; abnormal cell-cell junctions; failure of vascular remodelling.)
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 1 5 6 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Assertion made by the Aortopathy working group. Initial scoring curator was downsized. Case 1 was allocated only 1 pt based on the fact that the functional evidence was limited and that it was difficult to assess segregation with regards to TAA. Cases present with syndromic pathology (OPD/Melnick needles) and should not be given any points. Of the remaining female cases, most have neurological problems. FLNA causes cardiac valvular dysplasia with low risk for thoracic aortic disease and primarily diagnosed based on non-vascular features