SCNN1G

protein-coding

sodium channel epithelial 1 subunit gamma, 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 gamma subunit, and mutations in this gene have been associated with Liddle syndrome. [provided by RefSeq, Apr 2009]

MANE transcript

NM_001039.4

Inheritance

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

ClinVar variants

P:19U:182B:70

Top phenotype

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

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr16:23,182,745-23,216,883

External References & Databases

Ensembl (ENSG00000166828)

Transcript & Mutation Effects

hg38 • Region Span ~34.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Liddle syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008323

Submitter: ClinGen

The *SCNN1G* gene is located on chromosome 16 at p12.2 and encodes the gamma subunit of the epithelial sodium channel (ENaC). The epithelial sodium channel is a heteromeric complex composed of the gamma subunit and two additional homologous subunits; alpha and beta, encoded by the *SCNN1A* and *SCNN1B* genes, respectively. 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). It is crucial for Na+ reabsorption and, thus, electrolyte homeostasis (Hanukoglu 2016, PMID: 26772908). *SCNN1G* mutation was first reported in association with autosomal dominant Liddle Syndrome in 1995 (Hansson PMID:7550319). Liddle syndrome is characterized by early-onset (teenage) salt-sensitive hypertension. Laboratory evaluation shows hypokalemia, metabolic alkalosis, suppressed plasma renin activity and low plasma aldosterone (Tetti 2018 PMID: 29534496). *SCNN1G* mutation has also been reported in association with the autosomal recessive condition, Pseudohypoaldosteronism type I, and a Cystic Fibrosis-like condition referred to as ‘Bronchiectasis with or without elevated sweat chloride 3’ with an unclear inheritance pattern. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was sufficient phenotypic variability and differences in the molecular mechanisms to support splitting these disorders into three distinct disease entities; Liddle Syndrome (OMIM:618114), Pseudohypoaldosteronism type I (OMIM:264350) and Bronchiectasis with or without elevated sweat chloride 3 (OMIM:613071). Autosomal recessive Pseudohypoaldosteronism type I has been curated separately. At least seven unique variants across as many publications have been reported in *SCNN1G* in association with Liddle Syndrome. Six of these variants cause a late truncation eliminating the PY domain and the seventh is a missense variant within the PY domain. Degradation of the protein via the ubiquitination-proteasomal pathway is mediated through the PY domain and loss of this domain allows the accumulation of ENaC in the distal nephron apical membrane leading to an increase in sodium reabsorption (Rotin 2008 PMID: 18691017). Probands with Liddle Syndrome and their families described in the literature display a consistent phenotype with variable expressivity and almost complete penetrance as one family displayed normokalemia and one parent, positive for the familial variant, was unaffected (Fan P 2020 PMID: 32161960). In addition, this gene-disease association is supported by expression studies and *in vitro* functional assays. The protein product has also been identified to co-localize with, bind to, and function with SCNN1B and SCNN1A (Duc 1994 PMID: 7806569, Stewart 2011. PMID: 21775436, Schild 1995 PMID: 7777572). In summary, *SCNN1G* is definitively associated with autosomal dominant Liddle Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Liddle syndrome 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0020854

Submitter: Ambry Genetics

Liddle syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008323

Submitter: Orphanet

pseudohypoaldosteronism, type IB1, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: Orphanet

Liddle syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020854

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 recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: PanelApp Australia

Liddle syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020854

Submitter: PanelApp Australia

Liddle syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020854

Submitter: Labcorp Genetics (formerly Invitae)

pseudohypoaldosteronism, type IB1, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009917

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

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

Manifestation: Allergy/Immunology/Infectious; Pulmonary; Renal

Intervention: Allergy/Immunology/Infectious; Pulmonary; Renal

Rationale: In Pseudohypoaldosteronism, type I, 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 3, as in cystic fibrosis, early and aggressive pulmonary and other management (eg, related to prophylaxis and management of respiratory infections) may decrease morbidity

Refs: 7046191; 3550146; 3550146; 7550319; 8640238; 9649551; 10202170; 18507830; 19017867; 33690157

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCNN1G variants in ClinVar

12 Conditions Cataloged

not providedTotal: 154

Liddle syndrome 2Total: 131

Bronchiectasis with or without elevated sweat chloride 3Total: 110

Pseudohypoaldosteronism, type IB3, autosomal recessiveTotal: 95

Inborn genetic diseasesTotal: 70

not specifiedTotal: 56

Pseudohypoaldosteronism, type IB1, autosomal recessiveTotal: 36

SCNN1G-related disorderTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001039.4. 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	52 clinvar		62
missense			168 clinvar	18 clinvar		186
nonsense	3 clinvar	5 clinvar	2 clinvar			10
start loss						0
frameshift	3 clinvar	3 clinvar	2 clinvar			8
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar				5
Total	8	11	182	70	0	271

Highest pathogenic variant AF is 6.845602e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001039.4	RefSeq	NP_001030.2	12	MANE Select
ENST00000300061.3	Ensembl	ENSP00000300061.2	12	MANE Select
ENST00000876140.1	Ensembl	ENSP00000546199.1	11	Standard
ENST00000876141.1	Ensembl	ENSP00000546200.1	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 transport
excretion
sodium ion transmembrane transport
multicellular organismal water homeostasis
response to stimulus

Molecular Function

ion channel activity
sodium channel activity
protein binding
ligand-gated sodium channel activity
WW domain binding

Cellular Component

nucleoplasm
plasma membrane
integral component of plasma membrane
external side of plasma membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300061
Coding exons: 12
Length: 34169
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.561	328	358	0.916	0.0000232	4277
Missense (PolyPhen)		104	145.9	0.71283		1750
Synonymous	-0.492	152	144	1.05	0.00000980	1236
Loss of Function	4.12	7	32.2	0.217	0.00000159	374

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000053	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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 sweat glands. Also plays a role in taste perception. {ECO:0000269|PubMed:24124190, ECO:0000303|PubMed:7490094}.;
Disease: DISEASE: Liddle syndrome (LIDLS) [MIM:177200]: An autosomal dominant disorder characterized by hypertension, hypokalemic alkalosis, and suppression of plasma renin activity and aldosterone secretion. {ECO:0000269|PubMed:7550319}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bronchiectasis with or without elevated sweat chloride 3 (BESC3) [MIM:613071]: 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:18507830, ECO:0000269|PubMed:19017867}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.453

Intolerance Scores

LoFtool: 0.565
RVIS EVS: -0.95
RVIS percentile EVS: 9.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.893

Gene Damage Prediction

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