NM_000336.3(SCNN1B):c.1696C>T (p.Arg566Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 15, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000713386.10

Allele description [Variation Report for NM_000336.3(SCNN1B):c.1696C>T (p.Arg566Ter)]

NM_000336.3(SCNN1B):c.1696C>T (p.Arg566Ter)

Gene:

SCNN1B:sodium channel epithelial 1 subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_000336.3(SCNN1B):c.1696C>T (p.Arg566Ter)

Other names:

R564*

HGVS:

NC_000016.10:g.23380574C>T
NG_011908.1:g.83305C>T
NM_000336.3:c.1696C>TMANE SELECT
NP_000327.2:p.Arg566Ter
NC_000016.9:g.23391895C>T
NM_000336.2:c.1696C>T

Protein change:

R566*; ARG564TER

Links:

OMIM: 600760.0001; dbSNP: rs137852704

NCBI 1000 Genomes Browser:

rs137852704

Molecular consequence:

NM_000336.3:c.1696C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000843986	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Oct 15, 2021)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 14645220, 7954808, 24093724, 7777572, 27900368, 26075967, 27896928, 10362597, 28915228, 9576123, 11478429, 24474657, 26467025
SCV000948280	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 6, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7777572, 7954808, 28492532
SCV001766997	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 30, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000843986

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Oct 15, 2021)

unknown

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV000948280

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 6, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001766997

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 30, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Relative contribution of Nedd4 and Nedd4-2 to ENaC regulation in epithelia determined by RNA interference.

Snyder PM, Steines JC, Olson DR.

J Biol Chem. 2004 Feb 6;279(6):5042-6. Epub 2003 Nov 26.

PubMed [citation]

PMID:: 14645220

Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway.

Gille T, Randrianarison-Pellan N, Goolaerts A, Dard N, Uzunhan Y, Ferrary E, Hummler E, Clerici C, Planès C.

Am J Respir Cell Mol Biol. 2014 Mar;50(3):526-37. doi: 10.1165/rcmb.2012-0518OC.

PubMed [citation]

PMID:: 24093724

See all PubMed Citations (14)

Details of each submission

From Athena Diagnostics, SCV000843986.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This variant is expected to result in the loss of a functional protein. This variant results in a nonsense variant in the final exon of the gene which is not expected to trigger NMD, but which does eliminate the putatively important PY Motif. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown in studies to eliminate the protein domain needed for proper regulation, and thus greatly increase current through the sodium channel (PMID: 7777572).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000948280.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to result in constitutive hyperactivity of the SCNN1B sodium channel protein (PMID:7777572). This variant has been observed in several individuals with clinical features of Liddle syndrome (PMID:¬†27900368, 27896928, 26075967), and has been observed to segregate with Liddle syndrome in a family (PMID: 7954808).¬†This variant is also known as p.Arg564*¬†in the literature.¬†ClinVar contains an entry for this variant (Variation ID: 8830). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SCNN1B gene (p.Arg566*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acids of the SCNN1B protein.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001766997.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate that the variant results in increased sodium channel activity (Schild et al., 1995); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 75 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 7954808, 27896928, 27900368, 28915228, 7777572, 26075967, 9576123, 14645220)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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