Supravalvular aortic stenosis

Summary

Supravalvular aortic stenosis (MONDO:0008504) is a disease caused by ELN (GenCC Definitive), with 4 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: ELN (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,085
• Phenotypes (HPO): 7
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	13.3	Europe	Validated
Prevalence at birth	1-9 / 100 000	4	Europe	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0004381	Supravalvular aortic stenosis	Very frequent (80-99%)
HP:0011675	Arrhythmia	Very frequent (80-99%)
HP:0001279	Syncope	Frequent (30-79%)
HP:0001681	Angina pectoris	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0031664	Systolic heart murmur	Frequent (30-79%)
HP:0000822	Hypertension	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	supravalvular aortic stenosis
Mondo ID	MONDO:0008504
OMIM	185500
Orphanet	3193
DOID	DOID:1929
ICD-10-CM	Q25.3
ICD-11	1066595728
NCIT	C85176
SNOMED CT	268185002
UMLS	C0003499
MedGen	2001
GARD	0000743
MedDRA	10042598
Is cancer (heuristic)	no

Also known as: aortic supravalvular stenosis · supravalvar aortic stenosis · supravalvular aortic stenosis · supravalvular aortic stenosis (disease) · SVAS

Data availability: 1,085 ClinVar variants · 4 GenCC gene-disease records · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › aortic valve disorder › aortic valve stenosis › supravalvular aortic stenosis

Related subtypes (3): subvalvular aortic stenosis, congenital aortic valve stenosis, childhood aortic valve stenosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

246 uncertain significance, 176 likely benign, 73 pathogenic, 32 conflicting classifications of pathogenicity, 23 benign/likely benign, 22 benign, 17 likely pathogenic, 10 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
16733	NM_000501.4(ELN):c.[1034_1057dup;1741_1742delinsCA]		Pathogenic	no assertion criteria provided
1067515	NM_000501.4(ELN):c.82+1G>A	ELN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068837	NM_000501.4(ELN):c.348del (p.Gly117fs)	ELN	Pathogenic	criteria provided, single submitter
1071054	NM_000501.4(ELN):c.1191_1199del (p.Tyr397_Gly400delinsTer)	ELN	Pathogenic	criteria provided, single submitter
1071495	NM_000501.4(ELN):c.82+1G>C	ELN	Pathogenic	criteria provided, single submitter
1071516	NC_000007.13:g.(?73471702)(73483040_?)del	ELN	Pathogenic	criteria provided, single submitter
1072853	NM_000501.4(ELN):c.8del (p.Gly3fs)	ELN	Pathogenic	criteria provided, single submitter
1076698	NM_000501.4(ELN):c.909_916del (p.Ala304fs)	ELN	Pathogenic	criteria provided, single submitter
1076945	NM_000501.4(ELN):c.948T>A (p.Tyr316Ter)	ELN	Pathogenic	criteria provided, single submitter
1254893	NM_000501.4(ELN):c.800-1G>A	ELN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320044	NM_000501.4(ELN):c.582del (p.Phe195fs)	ELN	Pathogenic	criteria provided, single submitter
1322822	NM_000501.4(ELN):c.2032+1G>A	ELN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1359460	NM_000501.4(ELN):c.1393dup (p.Ala465fs)	ELN	Pathogenic	criteria provided, single submitter
1381578	NM_000501.4(ELN):c.96del (p.Ile33fs)	ELN	Pathogenic	criteria provided, single submitter
1382426	NM_000501.4(ELN):c.1351A>T (p.Lys451Ter)	ELN	Pathogenic	criteria provided, single submitter
1445727	NM_000501.4(ELN):c.1168G>T (p.Gly390Ter)	ELN	Pathogenic	criteria provided, single submitter
1454234	NM_000501.4(ELN):c.1075_1082dup (p.Ala362fs)	ELN	Pathogenic	criteria provided, single submitter
1458249	NM_000501.4(ELN):c.166del (p.Leu56fs)	ELN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459864	NC_000007.13:g.(?73461985)(73483030_?)del	ELN	Pathogenic	criteria provided, single submitter
163381	NM_000501.4(ELN):c.43dup (p.Leu15fs)	ELN	Pathogenic	criteria provided, single submitter
163382	NM_000501.4(ELN):c.131del (p.Pro44fs)	ELN	Pathogenic	criteria provided, single submitter
163383	NM_000501.4(ELN):c.435del (p.Leu146fs)	ELN	Pathogenic	criteria provided, single submitter
163387	NM_000501.4(ELN):c.800-2A>G	ELN	Pathogenic	criteria provided, multiple submitters, no conflicts
163388	NM_000501.4(ELN):c.862dup (p.Ala288fs)	ELN	Pathogenic	criteria provided, multiple submitters, no conflicts
163389	NM_000501.4(ELN):c.1097-1G>A	ELN	Pathogenic	criteria provided, single submitter
163397	NM_000501.4(ELN):c.1858G>T (p.Gly620Ter)	ELN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
163398	NM_000501.4(ELN):c.1918+1G>A	ELN	Pathogenic	criteria provided, single submitter
16719	ELN, 100-KB DEL	ELN	Pathogenic	no assertion criteria provided
16722	NM_000501.4(ELN):c.1324C>T (p.Gln442Ter)	ELN	Pathogenic	criteria provided, multiple submitters, no conflicts
16723	NM_000501.4(ELN):c.1621C>T (p.Arg541Ter)	ELN	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ELN	Definitive	Autosomal dominant	supravalvular aortic stenosis	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ELN	Orphanet:3193	Supravalvular aortic stenosis
ELN	Orphanet:90348	Autosomal dominant cutis laxa
ELN	Orphanet:904	Williams syndrome
ELN	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
METTL27	Orphanet:904	Williams syndrome
HRAS	Orphanet:146	Differentiated thyroid carcinoma
HRAS	Orphanet:2612	Linear nevus sebaceus syndrome
HRAS	Orphanet:2874	Phakomatosis pigmentokeratotica
HRAS	Orphanet:3071	Costello syndrome
HRAS	Orphanet:79414	Woolly hair nevus

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ELN	HGNC:3327	ENSG00000049540	P15502	Elastin	gencc,clinvar
METTL27	HGNC:19068	ENSG00000165171	Q8N6F8	Methyltransferase-like protein 27	clinvar
ELN-AS1	HGNC:40212	ENSG00000232415		ELN antisense RNA 1	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ELN	Elastin	Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ELN	Other/Unknown	no		Tropoelastin
METTL27	Other/Unknown	no		SAM-dependent_MTases_sf, Methyltransf_25
ELN-AS1	Other/Unknown	no
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ascending aorta	2
descending thoracic aorta	2
thoracic aorta	2
olfactory segment of nasal mucosa	1
primordial germ cell in gonad	1
right uterine tube	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ELN	227	broad	marker	descending thoracic aorta, ascending aorta, thoracic aorta
METTL27	159	ubiquitous	marker	right uterine tube, primordial germ cell in gonad, olfactory segment of nasal mucosa
ELN-AS1	125	broad	marker	descending thoracic aorta, ascending aorta, thoracic aorta
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HRAS	8,064
ELN	2,692
METTL27	1,591
ELN-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HRAS	P01112	246

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
METTL27	Q8N6F8	83.31
ELN	P15502	36.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 71. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by RAS GAP mutants	1	1903.3×	0.007	HRAS
Signaling by RAS GTPase mutants	1	1903.3×	0.007	HRAS
Activation of RAS in B cells	1	1142.0×	0.007	HRAS
RAS signaling downstream of NF1 loss-of-function variants	1	815.7×	0.007	HRAS
Estrogen-stimulated signaling through PRKCZ	1	815.7×	0.007	HRAS
SOS-mediated signalling	1	713.8×	0.007	HRAS
Activated NTRK3 signals through RAS	1	634.4×	0.007	HRAS
EGFR Transactivation by Gastrin	1	571.0×	0.007	HRAS
SHC-related events triggered by IGF1R	1	571.0×	0.007	HRAS
Activated NTRK2 signals through RAS	1	571.0×	0.007	HRAS
MET activates RAS signaling	1	519.1×	0.007	HRAS
Signaling by FGFR4 in disease	1	475.8×	0.007	HRAS
Activated NTRK2 signals through FRS2 and FRS3	1	475.8×	0.007	HRAS
Constitutive Signaling by Overexpressed ERBB2	1	475.8×	0.007	HRAS
p38MAPK events	1	439.2×	0.007	HRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	439.2×	0.007	HRAS
Signaling by PDGFRA extracellular domain mutants	1	439.2×	0.007	HRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	407.9×	0.007	HRAS
GRB2 events in EGFR signaling	1	380.7×	0.007	HRAS
Erythropoietin activates RAS	1	380.7×	0.007	HRAS
Signaling by FLT3 ITD and TKD mutants	1	380.7×	0.007	HRAS
SHC1 events in ERBB4 signaling	1	356.9×	0.007	HRAS
SHC1 events in EGFR signaling	1	356.9×	0.007	HRAS
Constitutive Signaling by EGFRvIII	1	356.9×	0.007	HRAS
Signalling to RAS	1	335.9×	0.007	HRAS
Insulin receptor signalling cascade	1	335.9×	0.007	HRAS
Signaling by ERBB2 ECD mutants	1	335.9×	0.007	HRAS
GRB2 events in ERBB2 signaling	1	317.2×	0.007	HRAS
Tie2 Signaling	1	300.5×	0.007	HRAS
SHC-mediated cascade:FGFR3	1	300.5×	0.007	HRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
animal organ morphogenesis	2	191.5×	0.001	ELN, HRAS
positive regulation of miRNA metabolic process	1	2808.7×	0.009	HRAS
oncogene-induced cell senescence	1	1203.7×	0.011	HRAS
T-helper 1 type immune response	1	936.2×	0.011	HRAS
regulation of smooth muscle cell proliferation	1	648.1×	0.011	ELN
Schwann cell development	1	526.6×	0.011	HRAS
regulation of long-term neuronal synaptic plasticity	1	495.6×	0.011	HRAS
positive regulation of ruffle assembly	1	495.6×	0.011	HRAS
extracellular matrix assembly	1	468.1×	0.011	ELN
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	443.5×	0.011	HRAS
stress fiber assembly	1	383.0×	0.011	ELN
respiratory gaseous exchange by respiratory system	1	312.1×	0.011	ELN
defense response to protozoan	1	300.9×	0.011	HRAS
cellular response to gamma radiation	1	300.9×	0.011	HRAS
regulation of actin filament polymerization	1	290.6×	0.011	ELN
positive regulation of protein targeting to membrane	1	280.9×	0.011	HRAS
positive regulation of wound healing	1	263.3×	0.011	HRAS
blood circulation	1	255.3×	0.011	ELN
aortic valve morphogenesis	1	216.1×	0.012	ELN
adipose tissue development	1	200.6×	0.012	HRAS
fibroblast proliferation	1	195.9×	0.012	HRAS
intrinsic apoptotic signaling pathway	1	179.3×	0.013	HRAS
outflow tract morphogenesis	1	153.2×	0.013	ELN
positive regulation of fibroblast proliferation	1	147.8×	0.013	HRAS
cellular senescence	1	147.8×	0.013	HRAS
skeletal muscle tissue development	1	145.3×	0.013	ELN
myelination	1	125.8×	0.015	HRAS
positive regulation of epithelial cell proliferation	1	122.1×	0.015	HRAS
positive regulation of type II interferon production	1	112.3×	0.015	HRAS
insulin receptor signaling pathway	1	110.9×	0.015	HRAS

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
HRAS	LONAFARNIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HRAS	4	4
ELN	0	0
METTL27	0	0
ELN-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LONAFARNIB	4	HRAS
STALLIMYCIN	2	HRAS
L-778123 FREE BASE	1	HRAS
BMS-214662	1	HRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HRAS	48	Binding:45, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HRAS	3.6.5.2	small monomeric GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LONAFARNIB	4	HRAS
STALLIMYCIN	2	HRAS
L-778123 FREE BASE	1	HRAS
BMS-214662	1	HRAS

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HRAS
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ELN, METTL27, ELN-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ELN	0	—
METTL27	0	—
ELN-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT02706639	Not specified	COMPLETED	Williams Syndrome (WS) and Supravalvar Aortic Stenosis (SVAS) DNA and Tissue Bank
NCT02840448	Not specified	COMPLETED	Impact of Elastin Mediated Vascular Stiffness on End Organs