SCNN1A

protein-coding

sodium channel epithelial 1 subunit alpha, the group of Sodium channels epithelial

Gene summary

Nonvoltage-gated, amiloride-sensitive, sodium channels control fluid and electrolyte transport across epithelia in many organs. These channels are heteromeric complexes consisting of 3 subunits: alpha, beta, and gamma. This gene encodes the alpha subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2009]

Previous symbols:

SCNN1

MANE transcript

NM_001038.6

Inheritance

AR, AD, Digenic (with CFTR or other SCCN1 genes)

ClinVar variants

P:43U:226B:80

Top phenotype

Pseudohypoaldosteronism, type IB1; Liddle syndrome 3; Bronchiectasis with or without elevated sweat chloride 2

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr12:6,346,843-6,377,730

External References & Databases

Ensembl (ENSG00000111319)

Transcript & Mutation Effects

hg38 • Region Span ~30.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pseudohypoaldosteronism, type IB1, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: Orphanet

Liddle syndrome 3LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0029132

Submitter: Labcorp Genetics (formerly Invitae)

bronchiectasis with or without elevated sweat chloride 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013087

Submitter: PanelApp Australia

pseudohypoaldosteronism, type IB1, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: Ambry Genetics

pseudohypoaldosteronism, type IB1, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: Labcorp Genetics (formerly Invitae)

bronchiectasis with or without elevated sweat chloride 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013087

Submitter: Ambry Genetics

pseudohypoaldosteronism, type IB1, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: PanelApp Australia

Liddle syndrome 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0029132

Submitter: Ambry Genetics

bronchiectasis with or without elevated sweat chloride 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013087

Submitter: Labcorp Genetics (formerly Invitae)

Brugada syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Orphanet

Liddle syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008323

Submitter: Orphanet

pseudohypoaldosteronism, type IB1, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

pseudohypoaldosteronism, type IB1, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: ClinGen

The *SCNN1A* gene is located on chromosome 12 at p13.31 and encodes the alpha subunit of the epithelial sodium channel (ENaC), a heteromeric complex composed of three homologous subunits - α, β and γ, encoded by the *SCNN1A*, *SCNN1B* and *SCNN1G* genes, respectively. This sodium channel is crucial for Na+ reabsorption and, thus, electrolytes homeostasis (Hanukoglu 2016, PMID: 26772908). The channel is localized in the apical portion of epithelial cells of the distal nephron, distal colon, lung, and ducts of exocrine glands (Canessa 1994 PMID: 8107805). *SCNN1A* mutation was first reported in association with autosomal recessive pseudohypoaldosteronism (PHA) type I in 1996 (Chang PMID: 8589714), however, the first clinical description of PHA was of a 3-month-old with hyponatremia and hyperkalemia, who was resistant to aldosterone but responded to dietary salt supplementation (Cheek and Perry 1958, PMID: 13545877). PHA type 1 is characterized by excess loss of salt in the urine and high concentrations of sodium in sweat, stool, and saliva. Laboratory tests may show hyponatremia, hyperkalemia and increased plasma renin activity with high levels of aldosterone in the blood. Treatment for this condition involves aggressive salt replacement and control of hyperkalemia. *SCNN1A* mutation has also been reported in association with the autosomal dominant condition, Liddle Syndrome, and a Cystic Fibrosis-like condition referred to as ‘Bronchiectasis with or without elevated sweat chloride 2’ with an unclear inheritance pattern. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was sufficient phenotypic variability and differences in mode of inheritance and the molecular mechanisms to support splitting these disorders into three distinct disease entities; Liddle Syndrome (OMIM:618126), Pseudohypoaldosteronism type I (OMIM:264350) and Bronchiectasis with or without elevated sweat chloride 3 (OMIM:613021). Autosomal dominant Liddle Syndrome has been curated separately. At least 7 variants in *SCNN1A* have been associated with PHA type 1 including 6 loss-of-function (frameshifts and nonsense) variants and 1 missense variant (Chang 1996, PMID 8589714, Schaedel 1999, PMID 10586178, Welzel, 2013 PMID: 23416952). More variants may be available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence including, biochemical function (Garty and Plamer, 1997 PMID: 9114818) and protein interaction with the other ENaC family members (Stewart 2011, PMID: 21775436). In addition, expression studies show the three members of the channel co-expressed in the renal distal convoluted tubules, connecting tubules, cortical collecting ducts, and outer medullary collecting ducts in rats (Duc 1994, PMID: 7806569). An αENaC(−/−)Tg mouse model also exists, showing clinical features of severe PHA-1 with metabolic acidosis, urinary salt-wasting, growth retardation, and 50% mortality (Hummler, 1997 PMID: 9326675). In summary, SCNN1A is definitively associated with autosomal recessive pseudohypoaldosteronism type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classificaiton was approved by the ClinGen Tubulopathy GCEP on the meeting date 11/18/21 (SOP Version 8).

Clinical Genomic Database (CGD)

Pseudohypoaldosteronism, type IB1; Liddle syndrome 3; Bronchiectasis with or without elevated sweat chloride 2AD/AR/Digenic (with CFTR or other SCCN1 genes)

Manifestation: Allergy/Immunology/Infectious; Pulmonary; Renal

Intervention: Allergy/Immunology/Infectious; Pulmonary; Renal

Rationale: In Pseudohypoaldosteronism, type 1B1, treatment with electrolyte replacement and control of hyperkalemia can be effective; In Liddle syndrome, certain medications (eg, amiloride, triamterene, but not spironolactone) and dietary sodium restriction can effectively treat hypertension and hypokalemia; In Bronchiectasis with or without elevated sweat chloride 2, as in cystic fibrosis, early and aggressive pulmonary and other management (eg, related to prophylaxis and management of respiratory infections) may decrease morbidity

Refs: 8589714; 9654209; 10202170; 9462466; 19017867

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCNN1A variants in ClinVar

15 Conditions Cataloged

Pseudohypoaldosteronism, type IB1, autosomal recessiveTotal: 186

Bronchiectasis with or without elevated sweat chloride 2Total: 175

not providedTotal: 173

Liddle syndrome 3Total: 137

Inborn genetic diseasesTotal: 108

not specifiedTotal: 36

SCNN1A-related disorderTotal: 28

Renal tubulopathiesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001038.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	51 clinvar		61
missense	1 clinvar	4 clinvar	208 clinvar	25 clinvar	1 clinvar	239
nonsense	4 clinvar	3 clinvar	1 clinvar	1 clinvar		9
start loss			1 clinvar			1
frameshift	13 clinvar	8 clinvar	1 clinvar	1 clinvar		23
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar	5 clinvar	1 clinvar		16
Total	20	23	226	79	1	349

Highest pathogenic variant AF is 0.0001227216

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001038.6	RefSeq	NP_001029.1	12	MANE Select
ENST00000228916.7	Ensembl	ENSP00000228916.2	12	MANE Select
NM_001159575.2	RefSeq	NP_001153047.1	13	Standard
NM_001159576.2	RefSeq	NP_001153048.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aldosterone-regulated sodium reabsorption - Homo sapiens (human)
Taste transduction - Homo sapiens (human)
Diuretics Pathway, Pharmacodynamics
Polythiazide Action Pathway
Methyclothiazide Action Pathway

Biological Process

sodium ion transmembrane transport
multicellular organismal water homeostasis
response to stimulus
sensory perception of taste
sodium ion homeostasis

Molecular Function

protein binding
ligand-gated sodium channel activity
WW domain binding

Cellular Component

acrosomal vesicle
cytoplasm
plasma membrane
integral component of plasma membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360168
Coding exons: 12
Length: 30888
Individuals with no LoFs: 125626
Homozygous LoFs: 0
Heterozygous LoFs: 122
Defined: 125748
p: 0.000485

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.490	443	415	1.07	0.0000243	4728
Missense (PolyPhen)		146	151.71	0.96236		1768
Synonymous	-0.405	182	175	1.04	0.0000107	1457
Loss of Function	1.97	23	35.7	0.644	0.00000222	362

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0.00069	0.00069	rare
East Asian	0.0014	0.0014	notable
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00055	0.00051	rare
South Asian	0.00030	0.00029	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and eccrine sweat glands. Also plays a role in taste perception. {ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:8278374}.;
Disease: DISEASE: Pseudohypoaldosteronism 1, autosomal recessive (PHA1B) [MIM:264350]: A rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1B is a severe form involving multiple organ systems, and characterized by an often fulminant presentation in the neonatal period with dehydration, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive and weight loss. {ECO:0000269|PubMed:10586178, ECO:0000269|PubMed:15853823, ECO:0000269|PubMed:18634878}. Note=The disease is caused by mutations affecting the gene represented in this entry. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty (PubMed:18634878). {ECO:0000269|PubMed:18634878}.; DISEASE: Bronchiectasis with or without elevated sweat chloride 2 (BESC2) [MIM:613021]: A debilitating respiratory disease characterized by chronic, abnormal dilatation of the bronchi and other cystic fibrosis-like symptoms in the absence of known causes of bronchiectasis (cystic fibrosis, autoimmune diseases, ciliary dyskinesia, common variable immunodeficiency, foreign body obstruction). Clinical features include sub-normal lung function, sinopulmonary infections, chronic productive cough, excessive sputum production, and elevated sweat chloride in some cases. {ECO:0000269|PubMed:19462466}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.290

Intolerance Scores

LoFtool: 0.952
RVIS EVS: 0.27
RVIS percentile EVS: 70.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.644

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium